JP2022520631A - 3,6-Disubstituted-2-pyridinealdoxime skeleton - Google Patents

Abstract

The present invention relates to a compound of formula (I): TIFF2022520631000180.tif32144 [where R1, R2, and —XY— are specifically defined], or one of the pharmaceutically acceptable salts thereof. .. The invention also relates to the use of this compound in treatment and the process of preparing it. [Selection diagram] None

Description

The present invention relates to novel compounds having a 3,6-disubstituted-2-pyridinealdoxime skeleton. This compound may be useful in many therapeutic and non-therapeutic applications. The present invention also relates to compositions containing said compounds, in particular pharmaceutical compositions, and their use.

Organophosphorus nerve agents (OPNA) are chemical weapons agents (CWA) containing salin, soman, cyclosarin, tabun, O-ethyl = S- [2- (diisopropylamino) ethyl] = methylphosphonothioate (VX), and It is a highly toxic compound containing pesticides such as paraoxon, parathion, and tetraethylpyrophosphate (TEPP). These acute toxicities result from the irreversible inhibition of acetylcholinesterase (AChE) by its catalytic phosphorylation of serins, which prevents the enzyme from hydrolyzing acetylcholine (ACh). Accumulation of this neurotransmitter occurs at cholinergic synapses, causing permanent saturation of muscarinic and nicotinic receptors, eventually leading to seizures and respiratory arrest. Depending on the type and dose of OPNA, death can occur within minutes.

Due to the similarities between the chemical precursors of CWA and pesticides and the relatively simple chemical phenomena involved in their synthesis, studies to control the spread of these agents have had limited success. It proves that. Therefore, the development of effective countermeasures against OPNA addiction remains a difficult task to solve in order to protect and treat both civilian and military populations. Current treatments for OPNA addiction are atropine (an antimuscarinic drug) and diazepam (an anticonvulsant) and standard pyridinium oxime (pralidoxime or 2-PAM, trimedoxime, HI-6,) to reactivate AChE. It consists of administering a combination of obidoxime or HLo-7). Oxime attacks the phosphorus atom of phosphorylated serine and acts on OPNA-inhibited AChE, resulting in elimination of phosphonates and restoration of enzymatic catalytic activity. The hybrid reactivated compound has a pyridinium oxime-based structure bound to a potential ligand at the peripheral site of the enzyme called a peripheral site ligand (PSL). Its purpose is to increase the affinity of reactivating factors for AChE (see Mercey G. et al., Accounts of Chemical Research, 756-766, 2012, Vol. 45, No. 5).

The efficiency of the reactivation factor can be estimated by the secondary rate constant kr2 for reactivation, which is the maximum reactivation rate constant (kr) and the apparent dissociation constant of the reactivation factor-inhibiting AChE complex. It is the ratio with (K _D ).

At this time, none of the known oximes have been proven to be equally effective against all species of OPNA-inhibiting AChE.

A recent international application WO 2017/021319 discloses a bifunctional compound containing a specific peripheral site ligand (PSL) moiety of an aminoquinoline functional group, which has an affinity for _hAChE (ie lower KD) including toxicity. Improves sex, allowing them to be potent reactivating factors for human AChE inhibited by any species of organophosphorus compounds. However, these bifunctional compounds contain a hydroxyl group that may be present at the 3-position of the pyridine group. This hydroxyl group needs to be protected and deprotected during synthesis. In addition, the hydroxyl groups may be involved in the internal cyclization of the molecule.

Therefore, there is still a need for efficient compounds for therapeutic applications against OPNA poisoning, which are synthesized particularly quickly and easily on a large scale in high yields. These compounds need to be stable without any internal cyclization.

Surprisingly, we have now found that certain pyridinealdoxime compounds having hydrogen or a particular alkoxy group at the 3-position meet these requirements. Since these compounds are not particularly charged, they can easily cross the blood-brain barrier.

In fact, such compounds can be produced quickly, concisely and very easily. The obtained compound does not cause intramolecular cyclization and can be used for human treatment.

In particular, these compounds can be used as antidotes for OPNA poisoning or as antidotes for organophosphorus compounds due to their effective and rapid reactivation of hAChE. Without being bound by any theory, these molecules appear to selectively bind to the catalytic site of hAChE. These compounds exhibit a very high reactivation efficiency of AChE, which was particularly inhibited. The compound's oxime can be regenerated when the serine residue is dephosphorylated, so the compound can be used any number of times. These compounds are also agonists of the adenosine 2A receptor. As a result, these compounds treat inflammation; treat neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease; and treat cancer, and especially by the inhibitory activity of histone deacetylase (HDAC), to treat diabetes and / or pain. Can be used for treatment.

［式中、各種の基は、以下の詳細な説明に規定される通りである］
の化合物である。 Therefore, the first object of the present invention is the formula (I) :.

[In the formula, the various groups are as specified in the detailed description below]
It is a compound of.

Another object of the present invention is the process of preparing a compound of formula (I), in particular by the Sonogashira reaction, as detailed below.

Another object of the present invention is a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable support.

Another object of the present invention is the compound of the present invention used as a pharmaceutical product.

A further object of the present invention is a compound of the present invention used for the treatment of neuropathy and / or respiratory failure due to poisoning with at least one organic phosphorus nerve agent.

A further object of the present invention is a compound of the present invention used for the treatment of inflammation.

A further object of the invention is a compound of the invention used in the treatment of neurological disorders such as Alzheimer's disease or Parkinson's disease.

A further object of the present invention is a compound of the present invention used in the treatment of cancer.

A further object of the present invention is a compound of the present invention used in the treatment of diabetes.

A further object of the present invention is a compound of the present invention used for the treatment of pain.

［式中、
Ｒ１はＨ、あるいは直鎖状または環状（好ましくは芳香族系）のＣ₁－Ｃ₇アルコキシ基である。好ましくは、Ｒ１はメトキシまたはベンジルオキシである；
－Ｘ－Ｙ－は、－ＣＨ₂－（ＣＨ₂）_n－、－Ｃ≡Ｃ－、

であるか、あるいは
－Ｘ－Ｙ－はＢｒであり、かつＲ２は存在しない；
ｎは０～５の整数である；
Ｒ２は、アルキル、アリール、アラルキル、ヘテロアリール、－Ｒ３－Ｎ（Ｒ４）（Ｒ５）、以下に示すＡ基、Ｂ基、Ｃ基、およびＤ基から選択される基であり、ここで、Ａ基、またはＢ基、またはＣ基、またはＤ基は、アルキル基、好ましくはエチル基によって－Ｙ－Ｘ－に結合してもよい；

Ｒ３はＣ₁－Ｃ₄アルキル基であり、かつ
Ｒ４およびＲ５は同一または異なり、それぞれ独立してＨ、ナフチル基、５－フルオロキノリン－４－イル基、キノリン－４－イル基、または８－メトキシキノリン－４－イル基を表し、あるいは
Ｒ４およびＲ５は、窒素原子とともに４－ベンジル－ピペラジン－１－イル基または３，７－ジメチル－２，６－ジオキソ－２，３，６，７－テトラヒドロ－１Ｈ－プリン－１－イル基を形成する］
の化合物、またはその薬学的に許容される塩のうちの１種である。 The first object of the present invention is the formula (I) :.

[During the ceremony,
R1 is H, or a linear or cyclic (preferably aromatic) C1 _{- C7} alkoxy group. Preferably R1 is methoxy or benzyloxy;
-XY- is -CH _2- (CH ₂ ) _n- , -C≡C-,

Or -XY- is Br and R2 is absent;
n is an integer from 0 to 5;
R2 is a group selected from alkyl, aryl, aralkyl, heteroaryl, -R3-N (R4) (R5), A group, B group, C group, and D group shown below, where A. The group, or B group, or C, or D group may be attached to —X— by an alkyl group, preferably an ethyl group;

R3 is _a C1- _C4 alkyl group, and R4 and R5 are the same or different, and independently H, naphthyl group, 5-fluoroquinoline-4-yl group, quinoline-4-yl group, or 8-yl group. Represents a methoxyquinoline-4-yl group, or R4 and R5 together with a nitrogen atom are a 4-benzyl-piperazine-1-yl group or 3,7-dimethyl-2,6-dioxo-2,3,6,7- Forming a tetrahydro-1H-purine-1-yl group]
A compound of, or one of its pharmaceutically acceptable salts.

The binding point of the triazole group with respect to the -XY-regulation is indicated by an asterisk on each side of the triazole group.

Ａ基の《Ｂｚ》はベンゾイル、ずなわちＰｈ－Ｃ（＝Ｏ）－を示す。 The point of attachment of any one of the A to D moieties (as defined in R2) to the rest of the molecule of formula (I) is indicated by an asterisk.

<< Bz >> of the A group indicates benzoyl, that is, Ph-C (= O)-.

"Pharmaceutically acceptable salt" refers to any salt of a compound of formula (I) having an acid or base. The pharmaceutically acceptable salt may be hydrochloride.

Pyridinium salt may be produced using pyridine of formula (I) as the salt. For example, when R4 and / or R5 are the same or different and each independently represents a 5-fluoroquinoline-4-yl group, a quinoline-4-yl group, or an 8-methoxyquinoline-4-yl group. The groups may be complexed with HCl to produce 5-fluoro-4-quinolinium groups, 4-quinolinium groups, or 8-methoxy-4-quinolinium groups, respectively. Preferred pharmaceutically acceptable salts are 5-fluoro-4-quinolinium group, 4-quinolinium group, and 8-methoxy-4-quinolinium group.

The oxime of the compound of formula (I) may be labeled with one or more isotopes such as ¹⁵ N, ¹⁸ O, ² H, or ³ H. In fact, such stable, non-toxic and non-radioactive isotopes will enable in-vivo and in-vitro biological studies.

"Alkyl" is preferably a linear hydrocarbon group containing 1 to 20 carbon atoms, particularly 1 to 15 carbon atoms, or a branched or cyclic hydrocarbon containing 3 to 20 carbon atoms. Indicates a hydrogen group. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-tridecyl, cyclohexyl, and cyclohexylmethyl groups. Preferred are ethyl, propyl, n-hexyl, n-tridecyl, cyclohexyl, or cyclohexylmethyl groups.

C ₁ -C ₄ alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

The "linear C ₁ -C ₇ alkoxy group" refers to a Rad-O- group, where Rad is a linear C ₁ -C ₇ alkyl group. Preferably, the _linear C1 _- C7 alkoxy group is methoxy.

The "cyclic (preferably aromatic) C ₁ -C ₇ alkoxy group" refers to a Rad-O- group, where Rad is a cyclic (preferably aromatic) C ₁ -C ₇ alkyl group. Preferably, the cyclic C ₁ -C ₇ alkoxy group is an aromatic C ₁ -C ₇ alkoxy group, more preferably benzyloxy.

"Aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group, which may be substituted as required. Preferably, the aryl group is phenyl, or a polycyclic aromatic hydrocarbon (PAH). The preferred PAH is pyrene. Aryl may be substituted with at least one alkyl group and / or at least one cyano group (-CN). A preferred example of an aryl group is phenyl.

"Aralkyl" refers to an aryl group as described above linked to a compound of formula (I) by an alkyl group. Preferably, the aralkyl group is phenylpropyl. In aralkyl, the aryl group may be substituted with at least one alkyl group and / or at least one cyano group (-CN). Preferably, the aralkyl is phenylpropyl.

"Heteroaryl" refers to an aryl group in which at least one carbon atom of the aromatic ring is substituted with a heteroatom, which may be optionally substituted. The heteroatom may be nitrogen, oxygen, phosphorus, or sulfur. Preferably, the heteroatom is nitrogen. Examples of heteroaryl groups include pyrrole, thiophene, furan, pyridine, pyrimidine, pyrazine, triazine, imidazole, thiazole, oxazole, and isoxazole groups. Preferably, the heteroaryl group is a pyridine group such as 4- or 3-pyridino. Heteroaryl may be substituted with at least one alkyl group and / or at least one cyano group (-CN). Preferably, the heteroaryl group is in salt form, preferably a pyridinium group such as 4- or 3-pyridinium.

According to the first embodiment, in the formula (I), it is preferable that —XY— is Br and R2 is absent.

［式中、Ｒ１は上記で規定された通りである］
を有する。 Thus, one of the compounds of formula (I) or their pharmaceutically acceptable salts is described in Skeleton 1:

[In the formula, R1 is as specified above]
Have.

In the compound of Skeleton 1, R1 is H, or a linear or cyclic (preferably aromatic) C ₁ -C ₇ alkoxy group. Preferably, in the compound of backbone 1, R1 is H, methoxy, or benzyloxy.

［式中、Ｒ１およびＲ２は上記で規定された通りである］
が好ましい。 According to the second embodiment, in the formula (I), -XY- is -C≡C- (skeleton 2) :.

[In the formula, R1 and R2 are as specified above]
Is preferable.

好ましくはＣ基またはＤ基は、アルキル基、より好ましくはエチル基によって－Ｙ－Ｘ－に連結されている。 The compound of skeleton 2 is a bifunctional compound.
Preferably, in the compound of backbone 2, R1 is selected from H and methoxy.
Preferably, in the compound of backbone 2, R2 is selected from A, B, C, and D groups.

Preferably the C or D group is linked to —X— by an alkyl group, more preferably an ethyl group.

Alternatively, preferably in the compound of Skeleton 2, R2 is alkyl, heteroaryl, aralkyl, or -R3-N (R4) (R5).
R3 is a C ₁ -C ₄ alkyl group, preferably R3 is selected from methyl, ethyl, and n-propyl.
R4 is H
R5 is selected from a naphthyl group, a 5-fluoroquinoline-4-yl group, a quinoline-4-yl group, or an 8-methoxyquinoline-4-yl group.

Alternatively, preferably in the compound of backbone 2, R2 is -R3-N (R4) (R5), R3 is _a C1- _C4 alkyl group, and preferably R3 is methyl, ethyl, and n-propyl. Selected from
R4 and R5, along with the nitrogen atom, are 4-benzyl-piperazine-1-yl groups or 3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-1-yl. Form a group.

Compounds of skeleton 2 have pKa due to increased affinity compared to compounds that do not have triple bonds and have -OH as R1 and compared to reference molecules such as pralidoxime (2-PAM) and HI-6. And increase in reactivation efficiency (kr2: / mM · min).

［式中、Ｒ１およびＲ２は上記で規定された通りである］
であることが好ましい。 According to the third embodiment, in the formula (I), -XY- is -CH _2- (CH ₂ ) _n- (where n is an integer of 0 to 5) (skeleton 3) :. ..

[In the formula, R1 and R2 are as specified above]
Is preferable.

The compound of skeleton 3 is a bifunctional compound.
Preferably, in the compound of backbone 3, R1 is selected from H and methoxy.
Preferably, in the compound of backbone 3, R2 is alkyl, aryl, aralkyl, or -R3-N (R4) (R5), where.
R3 is a C ₁ -C ₄ alkyl group, preferably R3 is selected from methyl, ethyl, and n-propyl.
R4 is H
R5 is selected from a naphthyl group, a 5-fluoroquinoline-4-yl group, a quinoline-4-yl group, or an 8-methoxyquinoline-4-yl group.

Alternatively, preferably in the compound of skeleton 3, R2 is —R3-N (R4) (R5), where R3 is _a C1- _C4 alkyl group, preferably R3 is methyl, ethyl, and n. Selected from -propyl, and R4 and R5 form a 4-benzyl-piperazine-1-yl group with a nitrogen atom.

であること（骨格４）：

［式中、Ｒ１およびＲ２は上記で規定された通りである］
が好ましい。 According to the fourth embodiment, in the formula (I), -XY- is

Being (skeleton 4):

[In the formula, R1 and R2 are as specified above]
Is preferable.

好ましくはＣ基またはＤ基は、アルキル基、より好ましくはエチル基によって－Ｙ－Ｘ－に連結されている。 The compound of skeleton 4 is a trifunctional compound.
Preferably, in the compound of skeleton 4, R1 is selected from H, methoxy, and benzyloxy, preferably R1 is H.
Preferably, in the compound of backbone 4, R2 is selected from A, C, and D groups.

Preferably the C or D group is linked to —X— by an alkyl group, more preferably an ethyl group.

The compound of Skeleton 4 selectively targets the catalytic site of hAChE and exhibits very good reactivation kinetics.

６－（５－フェニルペンタ－１－イン－１－イル）ピコリンアルデヒドオキシム ５：

６－（５－フェニルペンチル）ピコリンアルデヒドオキシム ７：

６－（ペンタデカ－１－イン－１－イル）ピコリンアルデヒドオキシム ９：

６－ペンタデシルピコリンアルデヒドオキシム １０：

６－（ピリジン－３－イルエチニル）ピコリンアルデヒドオキシム １２：

２－（（ヒドロキシイミノ）メチル）－６－（ピリジン－１－イウム－３－イルエチニル）ピリジン－１－イウムクロリド １３：

Ｎ－（４－｛６－［（ヒドロキシイミノ）メチル］ピリジン－２－イル｝ブタ－３－イン－１－イル）ナフタレン－１－アミン １９：

Ｎ－（４－｛６－［（ヒドロキシイミノ）メチル］ピリジン－２－イル｝ブタ－３－イン－１－イル）ナフタレン－１－アミン ２０：

６－（４－（キノリン－４－イルアミノ）ブタ－１－イン－１－イル）ピコリンアルデヒドオキシム ２５：

３－ヒドロキシ－６－（４－（キノリン－４－イルアミノ）ブチル）ピコリン酸メチル ２６：

６－（４－（（５－フルオロキノリン－４－イル）アミノ）ブタ－１－イン－１－イル）ピコリンアルデヒドオキシム ３０：

６－（４－（（５－フルオロキノリン－４－イル）アミノ）ブチル）ピコリンアルデヒドオキシム ３１：

６－（４－（（８－メトキシキノリン－４－イル）アミノ）ブタ－１－イン－１－イル）ピコリンアルデヒドオキシム ３６：

６－（４－（（８－メトキシキノリン－４－イル）アミノ）ブチル）ピコリンアルデヒドオキシム ３７：

６－（３－（４－ベンジルピペラジン－１－イル）プロパ－１－イン－１－イル）ピコリンアルデヒドオキシム ４２：

６－（３－（４－ベンジルピペラジン－１－イル）プロピル）ピコリンアルデヒドオキシム ４３：

６－（４－（４－ベンジルピペラジン－１－イル）ブタ－１－イン－１－イル）ピコリンアルデヒドオキシム ４７：

６－（４－（４－ベンジルピペラジン－１－イル）ブチル）ピコリンアルデヒドオキシム ４８：

６－（４－（３，７－ジメチル－２，６－ジオキソ－２，３，６，７－テトラヒドロ－１Ｈ－プリン－１－イル）ブタ－１－イン－１－イル）ピコリンアルデヒドオキシム ５１：

（３ａＳ、４Ｓ、６Ｒ、６ａＲ）－６－（６－アミノ－９Ｈ－プリン－９－イル）－Ｎ－（４－（６－（ヒドロキシイミノ）メチル）ピリジン－２－イル）ブタ－３－イン－１－イル）－２，２－ジメチルテトラヒドロフロ［３，４－ｄ］［１，３］ジオキソール－４－カルボキサミド ５６：

（２Ｓ、３Ｓ、４Ｒ、５Ｒ）－５－（６－アミノ－９Ｈ－プリン－９－イル）－３，４－ジヒドロキシ－Ｎ－（４－（６－（ヒドロキシイミノ）メチル）ピリジン－２－イル）ブタ－３－イン－１－イル）テトラヒドロフラン－２－カルボキサミド ５７：

Ｎ－（９－（（３ａＲ、４Ｒ、６Ｒ、６ａＲ）－６－（（（３－（６－（ヒドロキシイミノ）メチル）ピリジン－２－イル）プロパ－２－イン－１－イル）オキシ）メチル）－２，２－ジメチルテトラヒドロフロ［３，４－ｄ］［１，３］ジオキソール－４－イル）－９Ｈ－プリン－６－イル）ベンズアミド ６０：

６－（３－（（（３ａＲ、４Ｒ、６Ｒ、６ａＲ）－６－（６－アミノ－９Ｈ－プリン－９－イル）－２，２－ジメチルテトラヒドロフロ［３，４－ｄ］［１，３］ジオキソール－４－イル）メトキシ）プロパ－１－イン－１－イル）ピコリンアルデヒドオキシム ６１：

３－メトキシ－６－（５－フェニルペンタ－１－イン－１－イル）ピコリンアルデヒドオキシム ６４：

３－メトキシ－６－（５－フェニルペンチル）ピコリンアルデヒドオキシム ６５：

３－メトキシ－６－（４－（キノリン－４－イルアミノ）ブタ－１－イン－１－イル）ピコリンアルデヒドオキシム ６７：

４－（（４－（６－（（ヒドロキシイミノ）メチル）－５－メトキシピリジン－２－イル）ブタ－３－イン－１－イル）アミノ）キノリン－１－イウムクロリド ６８：

３－メトキシ－６－（４－（キノリン－４－イルアミノ）ブチル）ピコリンアルデヒドオキシム ６９：

４－（（４－（６－（（ヒドロキシイミノ）メチル）－５－メトキシピリジン－２－イル）ブチル）アミノ）キノリン－１－イウム ７０：

（３ａＳ、４Ｓ、６Ｒ、６ａＲ）－６－（６－アミノ－９Ｈ－プリン－９－イル）－Ｎ－（４－（６－（－（ヒドロキシイミノ）メチル）－５－メトキシピリジン－２－イル）ブタ－３－イン－１－イル）－２，２－ジメチルテトラヒドロフロ［３，４－ｄ］［１，３］ジオキソール－４－カルボキサミド ７２：

（３ａＳ、４Ｓ、６Ｒ、６ａＲ）－６－（６－アミノ－９Ｈ－プリン－９－イル）－Ｎ－（２－（１－（（６－（－（ヒドロキシイミノ）メチル）ピリジン－２－イル）メチル）－１Ｈ－１，２，３－トリアゾール－４－イル）エチル）－２，２－ジメチルテトラヒドロフロ［３，４－ｄ］［１，３］ジオキソール－４－カルボキサミド ７７：

（２Ｓ、３Ｓ、４Ｒ、５Ｒ）－５－（６－アミノ－９Ｈ－プリン－９－イル）－３，４－ジヒドロキシ－Ｎ－（２－（１－（（６－（－（ヒドロキシイミノ）－メチル）ピリジン－２－イル）メチル）－１Ｈ－１，２，３－トリアゾール－４－イル）エチル）テトラヒドロフラン－２－カルボキサミド塩酸塩 ７８：

Ｎ－（９－（（３ａＲ、４Ｒ、６Ｒ、６ａＲ）－６－（（（１－（（６－（－（ヒドロキシイミノ）メチル）ピリジン－２－イル）メチル）－１Ｈ－１，２，３－トリアゾール－４－イル）メトキシ）メチル）－２，２－ジメチルテトラヒドロフロ［３，４－ｄ］［１，３］ジオキソール－４－イル）－９Ｈ－プリン－６－イル）ベンズアミド ７９：

より好ましくは、式（Ｉ）の化合物は、以下の化合物の中から選択される。
（２Ｓ、３Ｓ、４Ｒ、５Ｒ）－５－（６－アミノ－９Ｈ－プリン－９－イル）－３，４－ジヒドロキシ－Ｎ－（４－（６－（ヒドロキシイミノ）メチル）ピリジン－２－イル）ブタ－３－イン－１－イル）テトラヒドロフラン－２－カルボキサミド ５７：

６－（４－（キノリン－４－イルアミノ）ブタ－１－イン－１－イル）ピコリンアルデヒドオキシム ２５：

３－ヒドロキシ－６－（４－（キノリン－４－イルアミノ）ブチル）ピコリン酸メチル ２６：

（２Ｓ、３Ｓ、４Ｒ、５Ｒ）－５－（６－アミノ－９Ｈ－プリン－９－イル）－３，４－ジヒドロキシ－Ｎ－（２－（１－（（６－（－（ヒドロキシイミノ）－メチル）ピリジン－２－イル）メチル）－１Ｈ－１，２，３－トリアゾール－４－イル）エチル）テトラヒドロフラン－２－カルボキサミド塩酸塩 ７８：

Preferably, the compound of formula (I) is selected from the following compounds and pharmaceutically acceptable salts thereof:
6-bromopicoline aldehyde oxime 2:

6- (5-Phenylpenta-1-in-1-yl) picoline aldehyde oxime 5:

6- (5-Phenylpentyl) picoline aldehyde oxime 7:

6- (Pentadeca-1-in-1-yl) Picoline aldehyde oxime 9:

6-Pentadecylpicoline aldehyde oxime 10:

6- (Pyridine-3-ylethynyl) Picoline Aldehyde Oxime 12:

2-((Hydroxyimino) Methyl) -6- (Pyridine-1-ium-3-ylethynyl) Pyridine-1-ium chloride 13:

N- (4- {6-[(hydroxyimino) methyl] pyridin-2-yl} buta-3-in-1-yl) naphthalene-1-amine 19:

N- (4- {6-[(hydroxyimino) methyl] pyridin-2-yl} buta-3-in-1-yl) naphthalene-1-amine 20:

6- (4- (quinoline-4-ylamino) pig-1-in-1-yl) picoline aldehyde oxime 25:

Methyl 3-hydroxy-6- (4- (quinoline-4-ylamino) butyl) picolinate 26:

6-(4-((5-Fluoroquinoline-4-yl) amino) buta-1-in-1-yl) picoline aldehyde oxime 30:

6-(4-((5-Fluoroquinoline-4-yl) amino) butyl) picoline aldehyde oxime 31:

6- (4-((8-Methoxyquinoline-4-yl) amino) buta-1-in-1-yl) picoline aldehyde oxime 36:

6-(4-((8-Methoxyquinoline-4-yl) amino) butyl) picoline aldehyde oxime 37:

6- (3- (4-Benzylpiperazine-1-yl) propa-1-in-1-yl) picoline aldehyde oxime 42:

6- (3- (4-Benzylpiperazine-1-yl) propyl) picoline aldehyde oxime 43:

6- (4- (4-Benzylpiperazine-1-yl) buta-1-in-1-yl) picoline aldehyde oxime 47:

6- (4- (4-Benzylpiperazine-1-yl) butyl) picoline aldehyde oxime 48:

6- (4- (3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-1-yl) pig-1-in-1-yl) picoline aldehyde oxime 51 :

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -N- (4- (6- (hydroxyimino) methyl) pyridin-2-yl) pig-3- In-1-yl) -2,2-Dimethyltetrahydroflo [3,4-d] [1,3] Dioxol-4-carboxamide 56:

(2S, 3S, 4R, 5R) -5- (6-amino-9H-purine-9-yl) -3,4-dihydroxy-N- (4- (6- (hydroxyimino) methyl) pyridin-2- Ill) Buta-3-in-1-yl) Tetrahydrofuran-2-carboxamide 57:

N- (9-((3aR, 4R, 6R, 6aR) -6-(((3- (6- (hydroxyimino) methyl) pyridin-2-yl) propa-2-in-1-yl) oxy) Methyl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] dioxol-4-yl) -9H-purine-6-yl) benzamide 60:

6-(3-(((3aR, 4R, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -2,2-dimethyltetrahydroflo [3,4-d] [1, 3] Dioxol-4-yl) methoxy) propa-1-in-1-yl) picoline aldehyde oxime 61:

3-Methoxy-6- (5-phenylpenta-1-in-1-yl) picoline aldehyde oxime 64:

3-Methoxy-6- (5-phenylpentyl) picoline aldehyde oxime 65:

3-Methoxy-6- (4- (quinoline-4-ylamino) buta-1-in-1-yl) picoline aldehyde oxime 67:

4-((4- (6-((Hydroxyimino) methyl) -5-methoxypyridin-2-yl) buta-3-in-1-yl) amino) quinoline-1-ium chloride 68:

3-Methoxy-6- (4- (quinoline-4-ylamino) butyl) picoline aldehyde oxime 69:

4-((4- (6-((Hydroxyimino) methyl) -5-methoxypyridin-2-yl) butyl) amino) quinoline-1-ium 70:

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -N- (4- (6-(-(hydroxyimino) methyl) -5-methoxypyridin-2- Il) Buta-3-in-1-yl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] Dioxol-4-carboxamide 72:

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -N- (2- (1-((6-(-(hydroxyimino) methyl) pyridine-2- Ile) Methyl) -1H-1,2,3-triazole-4-yl) Ethyl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] Dioxol-4-carboxamide 77:

(2S, 3S, 4R, 5R) -5- (6-amino-9H-purine-9-yl) -3,4-dihydroxy-N- (2- (1-((6- (-(hydroxyimino))) -Methyl) Pyridine-2-yl) Methyl) -1H-1,2,3-triazole-4-yl) Ethyl) Tetrahydrofuran-2-carboxamide hydrochloride 78:

N-(9-((3aR, 4R, 6R, 6aR) -6-(((1-((6-(-(hydroxyimino) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-Triazole-4-yl) methoxy) methyl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] dioxol-4-yl) -9H-purine-6-yl) benzamide 79:

More preferably, the compound of the formula (I) is selected from the following compounds.
(2S, 3S, 4R, 5R) -5- (6-amino-9H-purine-9-yl) -3,4-dihydroxy-N- (4- (6- (hydroxyimino) methyl) pyridin-2- Ill) Buta-3-in-1-yl) Tetrahydrofuran-2-carboxamide 57:

6- (4- (quinoline-4-ylamino) pig-1-in-1-yl) picoline aldehyde oxime 25:

Methyl 3-hydroxy-6- (4- (quinoline-4-ylamino) butyl) picolinate 26:

(2S, 3S, 4R, 5R) -5- (6-amino-9H-purine-9-yl) -3,4-dihydroxy-N- (2- (1-((6- (-(hydroxyimino))) -Methyl) Pyridine-2-yl) Methyl) -1H-1,2,3-triazole-4-yl) Ethyl) Tetrahydrofuran-2-carboxamide hydrochloride 78:

Preparation of compound of formula (I)

One of the compounds of formula (I) according to the invention or pharmaceutically acceptable salts thereof can be synthesized by any suitable method. For example, one of the compounds of formula (I) or pharmaceutically acceptable salts thereof may be prepared according to the following scheme.

The compound of the formula (I) of the skeleton 1, that is, the compound in which XY is Br is reacted with R2-XY-H (XY is -C≡C-) to obtain XY. Obtain a compound of formula (I) of skeleton 2 which is -C≡C-.
Next, by selective hydrogenation (according to H ₂ ), any compound (skeleton 3) of the formula (I) in which XY is −CH ₂ -CH _2- can be easily obtained.

To obtain the compound of Skeleton 4, the alkyne R2-C≡CH is reacted with the corresponding clickable reactivating agent by click chemistry.
Such methods are illustrated below.

Preparation of Compound of Formula (I) One of the compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof may be synthesized by any suitable method known to those skilled in the art.

Preferably, the compound of formula (I) is synthesized as described below. This process is chemically selective. In particular, the process does not require any of Oxime's past protection steps. The process comprises a minimum number of steps (1 or 2) and is carried out rapidly at ambient temperature.

ピコリンアルデヒド前駆体またはピコリノニトリル誘導体のいずれかとヒドロキシルアミン塩酸塩との、好ましくは有機溶媒中での反応によって得ることができる。すべての場合に、塩酸ヒドロキシルアミンは¹⁵Ｎ元素で標識してもよい。
この合成は、実施例中の６－ブロモピコリンアルデヒドオキシム２について示されている。 Skeleton 1
In particular, the compound of skeleton 1

It can be obtained by reaction of either a picoline aldehyde precursor or a picolinonitrile derivative with hydroxylamine hydrochloride, preferably in an organic solvent. In all cases, hydroxylamine hydrochloride may be labeled with ¹⁵ N elements.
This synthesis has been shown for 6-bromopicoline aldehyde oxime 2 in the examples.

Skeleton 2
In particular, the process of synthesizing skeleton 2 which is a compound of formula (I) is a sonogashira coupling reaction between a compound of skeleton 1, that is, a compound having 6-bromopyridine aldoxime and a terminal alkyne. It may include, and preferably consist of, the late stages. (See diagram above).
This Sonogashira coupling reaction was carried out in the presence of a solvent such as tetrahydrofuran (THF), triethylamine (Et ₃ N), or preferably a mixture thereof, and in the presence of catalysts such as Pd (PPh ₃ ) ₄ and CuI. You may.
This Sonogashira coupling reaction is carried out without any protection of the oxime moiety.

Skeleton 3
Next, the obtained alkyne (skeleton 2) is reacted with hydrogen in the presence of a Pd catalyst (such as Pd / C) and reduced to obtain the corresponding alkyl (skeleton 3) in a selective hydrogenation step. Can be done.
Even in this case, the hydrogenation step is carried out without any protection of the oxime moiety.

Skeleton 4
As described above and as shown in the scheme above, the alkyne R2-C≡CH is reacted with the corresponding clickable reactivating agent by click chemistry to obtain the compound of Skeleton 4.

Therefore, an object of the present invention is a process for preparing a compound of the formula (I), in which -XY- is -CH ₂ -CH _2- or -C≡C-, and R1 and R2. Is as defined above, and this process involves a sonogashira coupling reaction between 6-bromopyridine aldoxime and a compound having a terminal alkyne, and in some cases subsequently by reaction with hydrogen. Includes reduction step.

Use of the compounds of the invention in pharmaceuticals The compounds of the invention are preferably at least one that can be selected from weapons agents such as VX, tabun, sarin, cyclosarin, and soman, and pesticides such as paraoxon, parathion, and TEPP. It can be used to treat neuropathy and / or respiratory insufficiency due to poisoning with organophosphorus nerve agents. The compounds of the present invention can be used in the treatment of neuropathy and / or respiratory failure due to poisoning with at least one organophosphorus nerve agent due to their ability to reactivate organophosphorus-inhibited cholinesterase.

Alternatively, these compounds may be used to treat diseases with reduced acetylcholine production that can be overcome by administration of acetylcholinesterase inhibitors. Examples of such diseases include neurological diseases such as Alzheimer's disease and Parkinson's disease.

The compounds of the invention are also agonists of the adenosine 2A receptor. As a result, these compounds may be used in the treatment of inflammation, in the treatment of cancer, in the treatment of diabetes, and / or in the treatment of pain.

The compounds of the invention are typically included in pharmaceutical compositions comprising at least one compound of the invention and a pharmaceutically acceptable support.

The amount of one of the compounds of formula (I) or pharmaceutically acceptable salts thereof in the compositions of the invention may be extensively varied depending on the patient, mode of administration, and expected effect.

The compounds or compositions of the invention can be administered orally or parenterally, eg, via the external, parenteral, intramuscular, intravenous, skin, nasal, or rectal routes.

The pharmaceutical compositions of the present invention may include granules, powders, tablets, capsules, syrups, emulsions, suspensions, and forms used for parenteral administration such as injections, sprays, transdermal patches, or suppositories. May show the form of. These dosage forms may be prepared by known prior art.

Preparation of a solid dosage form to be orally administered may be carried out, for example, by the following process. Excipients (eg lactose, sucrose, starch, or mannitol), disintegrants (eg calcium carbonate, carboxymethyl cellulose calcium, alginic acid, sodium carboxymethyl cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, etc. Aluminum magnesium silicate, microcrystalline cellulose, cellulose powder, pregelatinized starch, sodium alginate, or alginate starch), excipients (eg, pregelatinized starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, alginic acid, Carbomer, dextrin, ethylcellulose, sodium alginate, maltodextrin, liquid glucose, aluminum magnesium silicate, hydroxyethylcellulose, methylcellulose, or guar gum), and lubricants (eg, talc, magnesium stearate, or polyethylene 6000) as active compounds. Add and then tablet the resulting mixture. If necessary, the tablets are coated with known techniques to distract the taste (eg, with cocoa powder, mint, borneol, or cinnamon powder) or to allow enteric or sustained release of the active compound. You may. Usable coating products include, for example, ethyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetophthalate, hydroxypropylmethyl cellulose phthalate, and Eudragit® (methacrylic acid-acrylic acid copolymer), Opadry (registered). Trademark) (hydroxypropyl methylcellulose + macrogol + titanium oxide + lactose monohydrate). A pharmaceutically acceptable colorant may be added (eg, yellow iron oxide, red iron oxide, or quinoline yellow pigment).

Liquid dosage forms for oral administration include solutions, suspensions, and emulsions. The aqueous solution may be obtained by dissolving the active ingredient in water and then adding a fragrance, a colorant, a stabilizer, and / or a thickener as needed. Ethanol, propylene glycol, or other pharmaceutically acceptable non-aqueous solvent can be added to improve solubility. Aqueous suspensions for oral use can be obtained by dispersing finely ground active ingredients in water, along with viscous products such as natural or synthetic gums or resins, methylcellulose, or sodium carboxymethylcellulose.

The dosage form for injection may be produced, for example, by the following steps. Dispersants (eg, eg olive oil, sesame seed oil, cottonseed oil, corn oil, or propylene glycol) in either an aqueous medium (eg, distilled water, physiological saline or Ringer's solution) or an oily medium (eg, olive oil, sesame seed oil, cottonseed oil, corn oil, or propylene glycol). Tween® 80, HCO® 60 (Nikko Chemicals), polyethylene glycol, carboxymethyl cellulose, or sodium alginate), preservatives (eg, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, Benzyl alcohol, chlorobutanol, or phenol), isotonic agents (eg, sodium chloride, glycerin, sorbitol, or glucose), and optionally solubilizers (eg, sodium salicylate or sodium acetate) or stabilizers (eg, sodium acetate). Dissolve, suspend, or emulsify with other additives such as human serum albumin).

Dosage forms for external use (topical use) may be obtained from solid, semi-solid, or liquid compositions containing the active compound. For example, to obtain a solid form, the active compound may be an excipient (eg, lactose, mannitol, starch, microcrystalline cellulose, or sucrose) and a thickener (eg, natural gum, cellulose derivative, or acrylic polymer). ) Can be processed and converted into powder. Liquid pharmaceutical compositions are prepared in substantially the same manner as injectable forms, as described above. The semi-solid pharmaceutical form is preferably in the form of an aqueous or oily gel, or in the form of pomade. These compositions may optionally include a pH regulator (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, or sodium hydroxide), and a preservative (eg, p-hydroxybenzoic acid ester, chlorobutanol, or chloride). Benzalconium) may be included.

Further described herein are methods of treating neuropathy and / or respiratory failure due to intoxication associated with at least one organophosphorus nerve agent, including administration of at least one compound of the invention.
Methods of treating neurological disorders such as Alzheimer's disease or Parkinson's disease, comprising administering at least one compound of the invention, are further described herein.
Methods of treating inflammation, including administering at least one compound of the invention, are further described herein.
Methods of treating cancer, comprising administering at least one compound of the invention, are further described herein.
Methods of treating diabetes, including administration of at least one compound of the invention, are further described herein.
Methods of treating pain, including administering at least one compound of the invention, are further described herein.

Within the context of the present invention, the term "treatment" refers to curative, symptomatic, and / or prophylactic treatment. In particular, the term may refer to slowing the progression of a disease, reducing or suppressing at least one of its symptoms or complications, or improving a patient's health in some way.

Administration of the compounds or compositions of the invention may be performed prior to, during or after exposure to the organophosphorus agent of interest.

In the present invention, the terms "subject" and "patient" are used interchangeably and refer to a human subject.

The amount of the compound of formula (I) or one pharmaceutically acceptable salt thereof administered in accordance with the present invention may be extensively varied depending on the patient, mode of administration, and expected effect. In particular, the compound of formula (I) or one pharmaceutically acceptable salt thereof may comprise 200 mg to 4000 mg in up to 3 daily doses.

The compounds or compositions of the invention capture and / or capture OPNA in blood, for example, antimuscarinic agents (particularly atropine), anticonvulsants (particularly diazepam such as avisaphone or a prodrug thereof), and / or. It may be co-administered with at least one other active agent that is a biocapture agent such as degradable human butyrylcholinesterase.

The term "co-administration" indicates that administration of a compound or composition of the invention and administration of other active agents may be simultaneous, continuous, and / or separate.

Other Uses of Compounds of the Invention The compounds of the invention may further be used as tools for in vivo and / or in vitro biological studies. In this application, the compounds of formula (I) or one of the pharmaceutically acceptable salts thereof may contain one or more isotopes that allow their detection.

The following examples are provided as examples of the present invention and are not limited thereto.

Example 1: Synthesis of the compound of the present invention
Synthesis of I-bifunctional pyridine aldoxime analog
Synthesis of 6- (5-phenylpentyl) picoline aldehyde oxime:

6-bromopicoline aldehyde oxime 2:

This compound was synthesized according to the paper published by L. Zhang et al. ¹ below. Hydroxylammonium hydrochloride (2.24 g, 32.3 mmol) and sodium acetate (2.65 g, 32.3 mmol) were added to an anhydrous EtOH solution (50 mL) of 6-bromopicoline aldehyde 1 (3.00 g, 16.1 mmol) at room temperature. After the addition, the colorless solution with the white suspension was stirred at 90 ° C. for 3 hours. The solution was cooled to room temperature and concentrated in vacuo. The resulting white solid was dissolved in EtOAc (50 mL). The organic layer was washed with H ₂ O (5 x 20 mL), dried (DDL ₄ ), filtered and concentrated in vacuo to give the title compound 2 (3.21 g, 16.0 mmol, 99%) a white solid. Got as. Physical and spectroscopic data are in agreement with reported value ¹ . Melting point 168-170 ° C (Reference ² 164-166 ° C); IR (neat method) ν _max 3203, 3084, 2912, 1546, 1158, 1119, 704 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.90 (s, 1H, CHNOH), 8.04 (s, 1H, CHNOH), 7.82-7.74 (m, 2H, NCCHCHCH, NCCHCHCH), 7.63 (dd, J = 6.8, 1.7 Hz, 1H, NCCHCHCH; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 153.3, 147.5, 141.0, 140.1, 128.1, 119.3; HRMS (ESI) ⁺ C ₆ H ₅ BrN ₂ O ⁺ m / z calculated value is 200.9658, actual measurement value is 200.9657.
References:
1. 1. Bioorg. Med. Chem. Lett. 2016, 26, 778-781

6- (5-Phenylpenta-1-in-1-yl) picoline aldehyde 4:

Pd [PPh ₃ ] ₄ (482 mg, 0.0.417 mmol, 0.15 eq) in a degassed THF / Et ₃ N (10 mL / 30 mL) solution of bromopiconaldehyde 1 (568 mg, 3.056 mmol, 1.1 eq). And CuI (159 mg, 0.834 mmol, 0.3 eq) were added. After degassing the reaction mixture at room temperature for 5 minutes, alkyne 3 (400 mg, 2.78 mmol, 1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. Upon completion (monitored by TLC), the reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography (from EtOAc / PE 6:94 to EtOAc / PE 1: 9) to the desired conjugated picon. Aldehyde 4 was obtained as a colorless oil (500 mg, 72%). R _f (20% EtOAc + PE) 0.65; IR (neat method) ν _max 3026, 2928, 2856, 2229, 1710, 1580, 1451, 1211, 987, 805, 698, 647, 542 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 9.99 (s, 1H, H ₁₈ ), 7.82-7.71 (m, 2H, H ₃ , H ₄ ), 7.53 (dd, J = 7.5 Hz, 1H, H ₅ ) ), 7.26-7.10 (m, 5H, H ₁₃ -H ₁₇ ), 2.74 (t, J = 7.5 Hz, 2H, H ₁₁ ), 2.43 (t, J = 7.1 Hz, 2H, H ₉ ), 1.92 (5) Heavy wire, J = 7.1, 7.5 Hz, 2H, H ₁₀ ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 193.09 (C18), 152.76 (C2), 144.43 (C6), 141.21 (C12), 137.21 (C4), 130.92 (C5), 128.47 (C14, C16), 128.41 (C13, C17), 126.02 (C15), 119.94 (C3), 92.32 (C7), 79.93 (C8), 34.90 (C11), 29.74 (C10), 18.81 (C9); HRMS (ESI) ⁺ C ₁₇ H ₁₆ NO ⁺ m / z calculated value is 250.1226, measured value is 250.1239.

6- (5-Phenylpenta-1-in-1-yl) picoline aldehyde oxime 5:

Method 1:
A dry ethanol solution (6 mL) of aldehyde 4 (100 mg, 0.402 mmol, 1 eq), hydroxylamine hydrochloride (56 mg, 0.803 mmol, 2 eq), and CH ₃ CO ₂ Na (100 mg, 1.206 mmol, 3 eq). ) Was refluxed and stirred for 16 hours. Upon completion (monitored by TLC), the solid is filtered off with a short Celite pad, the solvent is evaporated and the residue is purified by column chromatography (EtOAc / PE 1: 9) to whiten Oxime 5. Obtained as a solid (100 mg, 94%). R _f (20% EtOAc + PE) 0.35; IR (neat method) ν _max 3177, 3005, 2933, 2876, 2226, 1568, 1495, 1445, 1257, 1159, 985, 807, 734, 703, 657, 576 , 490 cm ^-1 ; ^{1 1} H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.85 (s. 1H, OH), 8.24 (s, 1H, H ₁₈ ), 7.68 (dd, J = 0.7, 7.8 Hz, 1H, H ₃ ), 7.56 (t, J = 7.8 Hz, 1H, H ₄ ), 7.29 (dd, J = 0.7, 7.7 Hz, 1H, H ₅ ), 7.29 to 7.08 (m, 5H, H ₁₃ -H) ₁₇ ), 2.71 (t, J = 7.5 Hz, 2H, H ₁₁ ), 2.39 (t, J = 7.1 Hz, 2H, H ₉ ), 1.89 (quintuplet, J = 7.1, 7.5 Hz, 2H, H ₁₀ ) ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 151.95 (C2), 150.51 (C18), 144.46 (C6), 141.33 (C12), 136.73 (C4), 128.50 (C14, C16), 128.35 ( C13, C17), 127.13 (C5), 125.92 (C15), 119.23 (C3), 91.47 (C7), 80.19 (C8), 34.84 (C11), 29.78 (C10), 18.77 (C9); HRMS (ESI) ⁺ The m / z calculated value of C ₁₇ H ₁₇ N ₂ O ₁ ⁺ is 265.1335, and the measured value is 265.1360.

Method 2:
Pd [PPh ₃ ] ₄ (60 mg, 0.052 mmol, 0.15 eq) and CuI (20 eq) in a degassed THF / Et ₃ N (5 mL / 2 mL) solution of oxime 2 (77 mg, 0.381 mmol, 1.1 eq). mg, 0.104 mmol, 0.3 eq) was added. After degassing the reaction mixture at room temperature for 5 minutes, alkyne 3 (50 mg, 0.347 mmol, 1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. Upon completion (monitored by TLC), the reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography (EtOAc / PE 1: 9) to give the desired bound oxime 5 to a white solid (68 mg). , 74%).

6- (5-Phenylpentyl) picoline aldehyde 6:

To a degassed dry EtOAc solution (4 mL) of 6-substituted piconaldehyde 4 (200 mg, 0.802 mmol, 1 eq) was added 10% Pd / C (21 mg, 0.201 mmol, 0.25 eq). After washing 3 times with H ₂ , the reaction mixture was stirred at room temperature under H ₂ (1 atm) for 90 minutes. Upon completion (monitored by TLC), filter through a short column of Celite to remove the catalyst, evaporate the solvent and purify the residue by column chromatography (EtOAc / PE 1: 9) to remove oxime 6. Obtained as a colorless liquid (185 mg, 91%). R _f (20% EtOAc + PE) 0.70; IR (neat method) ν _max 3026, 2929, 2856, 1709, 1591, 1455, 1213, 1089, 745, 689, 646, 570, 496 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 9.97 (s, 1H, H ₁₈ ), 7.73-7.63 (m, 2H, H _3, H ₄ ), 7.26 (dd, J = 1.5, 7.7 Hz, 1H, H ₅ ), 7.24 to 7.05 (m, 5H, H ₁₃ -H ₁₇ ), 2.80 (t, J = 7.7 Hz, 2H, H ₇ ), 2.54 (t, J = 7.7 Hz, 2H, H ₁₁ ), 1.73 (5-fold line, J = 7.7 Hz, 2H, H ₈ ), 1.60 (5-fold line, J = 7.7 Hz, 2H, H ₁₀ ), 1.35 (5-fold line, J = 7.3, 7.8 Hz, 2H, H ₉ ) ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 193.87 (C18), 163.12 (C6), 152.35 (C2), 142.50 (C12), 137.08 (C4), 128.33 (C14, C16), 128.20 ( C13, C17), 127.04 (C5), 125.60 (C15), 119.08 (C3), 37.99 (C7), 35.74 (C11), 31.20 (C10), 29.59 (C8), 28.84 (C9); HRMS (ESI) ⁺ The m / z calculated value of C ₁₇ H ₂₀ NO ⁺ is 254.1537, and the measured value is 254.1539.

6- (5-Phenylpentyl) picoline aldehyde oxime 7:

A dry ethanol solution (12 mL) of aldehyde 6 (150 mg, 0.592 mmol, 1 eq), hydroxylamine hydrochloride (82 mg, 1.184 mmol, 2 eq), and CH ₃ CO ₂ Na (146 mg, 1.77 mmol, 3 eq). ) Was refluxed and stirred for 16 hours. Upon completion (monitored by TLC), the solid is filtered off with a short Celite pad, the solvent is evaporated and the residue is purified by column chromatography (EtOAc / PE 1: 9) to the desired oxime 7. Obtained as a white solid (135 mg, 85%). R _f (20% EtOAc + PE) 0.40; IR (neat method) ν _max 3080, 2926, 2856, 1720, 1575, 1452, 1269, 986, 780, 699, 658, 569, 458 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 10.20 (br s, 1H, -OH), 8.30 (s, 1H, H ₁₈ ), 7.59 (br d, J = 8.0 Hz, 1H, H ₃ ), 7.50 (T, J = 7.8 Hz, 1H, H ₄ ), 7.27 to 6.93 (m, 6H, H ₅ , H ₁₃ -H ₁₇ ), 2.74 (t, J = 7.8 Hz, 2H, H ₇ ), 2.50 (t) , J = 7.5 Hz, 2H, H ₁₁ ), 1.68 (5-fold line, J = 7.5, 7.8 Hz, 2H, H ₈ ), 1.57 (5-fold line, J = 7.5 Hz, 2H, H ₁₀ ), 1.32 (5) 5 layers, J = 7.1, 7.8 Hz, 2H, H ₉ ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 162.23, * 160.10 (C6), 151.36, * 150.73 (C2), 150.40 (C18) ), 142.61, * 142.23 (C12), * 138.33, 136.97 (C4), * 129.46, 128.33 (C14, C16), 128.16 (C13, C17), 125.61, * 125.53 (C5), * 124.23, 123.01 (C15) , * 120.84, 118.112 (C3), 37.86, * 37.29 (C7), 35.75 (C11), 31.22, * 31.10 (C10), 29.82 (C8), 28.91, * 28.69 (C9) (* mixture of cis and trance) HRMS (ESI) ⁺ C ₁₇ H ₂₁ N ₂ O ⁺ m / z calculated value is 269.1648, measured value is 269.1670.

Synthesis of 6-pentadecylpicolinaldehyde oxime 10:

6- (Pentadeca-1-in-1-yl) Picoline aldehyde oxime 9:

Pd [PPh ₃ ] ₄ (42 mg, 0.036 mmol, 0.15 eq) and CuI (14) in a degassed THF / Et ₃ N (4 mL / 2 mL) solution of oxime 2 (51 mg, 0.252 mmol, 1.05 eq). mg, 0.072 mmol, 0.3 eq) was added. After degassing the reaction mixture at room temperature for 5 minutes, alkyne 8 (50 mg, 0.240 mmol, 1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. Upon completion (monitored by TLC), the reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography (EtOAc / PE 6:94) to give the desired bound oxime 9 to a white solid (65 mg). , 83%). R _f (20% EtOAc + PE) 0.55; IR (Neat Method) ν _max 3179, 3092, 2914, 2850, 2226, 1722, 1567, 1450, 1268, 1160, 992, 809, 733, 709, 657, 640 , 549, 496 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.50 (s, 1H, OH), 8.26 (s, 1H, H ₂₂ ), 7.72 (br d, J = 7.8 Hz) , 1H, H ₃ ), 7.61 (t, J = 7.8 Hz, 1H, H ₄ ), 7.23 (br d, J = 7.7 Hz, 1H, H ₅ ), 2.41 (t, J = 7.2 Hz, 2H, H) ₉ ), 1.61 (5-fold wire, J = 7.2 Hz, 2H, H ₁₀ ), 1.41 (m, 2H, H ₁ ), 1.24 (s, 18H, H ₁₂ -H ₂₀ ), 0.85 (t, J = 6.5) Hz, 3H, H ₂₁ ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 151.89 (C2), 150.73 (C22), 143.69 (C6), 136.64 (C4), 127.13 (C5), 125.92 (C15) ), 119.12 (C3), 92.10 (C7), 79.76 (C8), 31.91, 29.64, 29.49, 29.35, 29.13, 29.00, 28.31, 22.68, 19.40, 14.11 (C9-C21); HRMS (ESI) ⁺ C ₂₁ H The calculated value of ₃₃ N ₂ O ₁ ⁺ is 329.2587, and the measured value is 329.2549.

6-Pentadecylpicoline aldehyde oxime 10:

To a degassed dry EtOAc solution (2 mL) of Oxime 9 (35 mg, 0.107 mmol, 1 eq) was added 10% Pd / C (3 mg, 0.027 mmol, 0.25 eq). After washing 3 times with H ₂ , the reaction mixture was stirred at room temperature under H ₂ (1 atm) for 2 hours. Upon completion, the catalyst is removed by filtration through a short column of Celite, the solvent is evaporated, the residue is purified by column chromatography (EtOAc / PE 6:94) to purify Oxym 3 as a white solid (30 mg, 85). %); R _f (20% EtOAc + PE) 0.65; IR (neat method) ν _max 3187, 3083, 2914, 2849, 1575, 1457, 1160, 985, 777, 718, 656, 517, 479. cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.36 (br s, 1H, OH), 8.25 (s, 1H, H ₂₂ ), 7.61 to 6.54 (m, 2H, H _3, H) ₄ ), 7.11 (dd, J = 2.5, 6.1 Hz, 1H, H ₅ ), 2.78 (t, J = 7.2 Hz, 2H, H ₇ ), 1.70 (m, 2H, H ₈ ), 1.24 (s, 24H) , H ₁₂ -H ₂₀ ), 0.86 (t, J = 6.6 Hz, 1H, H ₂₁ ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 162.71 (C6), 151.12 (C2), 151.02 (C23) ), 136.73 (C4), 123.09 (C5), 118.21 (C3), 38.28, 31.92, 29.99, 29.69, 29.56, 29.49, 29.41, 29.36, 22.69, 14.12 (C7-C22); HRMS (ESI) ⁺ C ₂₁ H The m / z calculated value of ₃₇ N ₂ O ⁺ is 333.2900, and the measured value is 333.2918.

2-((Hydroxyimino) Methyl) -6- (Pyridine-1-ium-3-ylethynyl) Synthesis of Pyridine-1-ium Chloride 13:

3-Fluoro-6- (Pyridine-3-ylethynyl) Picoline Aldehyde Oxime 12:

Pd [PPh ₃ ] ₄ (173 mg, 0.15 mmol, 0.15 eq) and CuI (57 eq) in a degassed THF / Et ₃ N (3 mL / 3 mL) solution of oxime 2 (211 mg, 1.05 mmol, 1.05 eq). mg, 0.30 mmol, 0.3 eq) was added. After degassing the reaction mixture at room temperature for 5 minutes, a degassed dry THF (3 mL) solution of Alkin 11 (103 mg, 1 mmol, 1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. Upon completion (monitored by TLC), the reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography (EtOAc / PE 45:55) to give the desired bound oxime 12 as a white solid (200 mg). , 90%). R _f (60% EtOAc + PE) 0.35; IR (Neat Method) ν _max 3065, 2764 ^, 1578, 1561, 1443, 1288, 1143, 1042, 990, 981, 798, 697, 637, 563, 499 cm- ¹ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 11.84 (s, 1H, OH), 8.83 (br s, 1H, H ₁₄ ), 8.65 (br s, 1H, H ₁₂ ), 8.11 ~ 8.04 (m, 2H, H _10, H ₁₅ ), 7.91 (br t, J = 7.8 Hz, 1H, H ₄ ), 7.83 (br d, J = 7.8 Hz, 1H, H ₃ ), 7.68 (br d) , J = 7.8 Hz, 1H, H ₅ ), 7.50 (dd, J = 4.8, 7.8 Hz, 1H, H ₁₁ ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ (ppm) 152.855 (C2), 151.93 (C14), 149.70 (C12), 148.34 (C15), 141.51 (C6), 139.03 (C10), 137.65 (C4), 127.50 (C5), 123.78 (C11), 119.84 (C3), 118.48 (C9), 91.27 (C7), 85.48 (C8); HRMS (ESI) ⁺ C ₁₃ H ₁₀ N ₃ O ⁺ m / z calculated value is 224.0818, measured value is 224.0840.

2-((Hydroxyimino) Methyl) -6- (Pyridine-1-ium-3-ylethynyl) Pyridine-1-ium chloride 13:

To an aqueous solution (1 mL) of compound 12 (40 mg) was added 1.2N HCl (1 mL), stirred for 2 minutes and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give the HCl salt 13 as a white solid in quantitative yield. IR (neat method) ν _max 3018, 2970, 2502, 2080, 1561, 1465, 1290, 1005, 813, 726, 674, 548, 499 cm ^-1 ; ¹ H NMR (400 MHz, D ₂ O) δ (ppm) ) 9.05 (br s, 1H), 8.83 (br d, J = 5.8 Hz, 1H), 8.75 (dt d, J = 1.6, 8.3 Hz, 1H), 8.19 (s, 1H), 8.15 to 8.04 (m, 2H), 7.87 (dd, J = 0.6, 8.0 Hz, 1H), 7.81 (br d, J = 0.6, 7.8 Hz, 1H); ¹³ C NMR (100 MHz, D ₂ O) δ (ppm) 150.85, 149.74 , 148.30, 144.75, 142.04, 141.28, 139.9, 130.03, 128.12, 123.99, 122.81, 92.14, 85.20; HRMS (ESI) ⁺ C ₁₃ H ₁₀ N ₃ O ⁺ m / z calculated value is 224.0818, measured value is 224.0826.

Synthesis of 6- (4- (naphthalene-1-ylamino) butyl) picoline aldehyde oxime 20:

2- (naphthylamino) ethanol 15:

For the synthesis of substituted aromatic amines, follow the procedure of Couty et al. ¹ . In a solution of 1-iodonaphthalene 14 (2.50 g, 9.8 mmol), 2-aminoethanol (1.78 mL, 29.5 mmol), copper chloride (132 mg, 1.0 mmol) and freshly ground KOH (1.10 g, 19.7 mmol). DMSO solution (2 mL) was stirred at room temperature for 18 hours. A saturated aqueous solution of NH ₄ Cl (5 mL) was added to the brown shrimp solution, and this solution was extracted (EtOAc, 3 × 20 mL). The mixed extract was washed (brine, 20 mL), dried (DDL ₄ ), filtered and concentrated in vacuo. Chromatography of silica gel (30% EtOAc in light petroleum ether) gave the title compound 15 (1.68 g, 9.0 mmol) as a beige oil. IR (neat method) ν _max 3404, 3051, 2973, 2869, 1581, 785 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.93 to 7.76 (m, 2H, ArH), 7.52 to 7.29 (M, 4H, ArH), 6.67 (d, J = 7.3 Hz, 1H, CHCNH), 4.01 (t, J = 5.1 Hz, 2H, NHCH ₂ CH ₂ OH), 3.49 (t, J = 5.1 Hz, 2H) , NHCH ₂ CH ₂ OH); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 142.8, 134.6, 128.7, 126.4, 125.9, 125.0, 123.9, 120.0, 118.5, 105.5, 61.0, 46.6.

2-[(2-Hydroxyethyl) (naphthalene-1-yl) amino] acetonitrile 16:

For N-cyanomethylation of aromatic aminoethanol, follow the procedure of Couty et al. ¹ . A MeCN solution (20 mL) of 2- (naphthylamino) ethanol 15 (745 mg, 4.0 mmol) and paraformaldehyde (717 mg, 8.0 mmol) was heated at 90 ° C for 18 hours. The white suspension was cooled to room temperature, TMSCN (1.06 mL, 8.0 mmol) and AcOH (0.46 mL, 8.0 mmol) were added to the reaction, and the pale yellow reaction solution was stirred at 90 ° C for 18 hours. The reaction was cooled to room temperature, H ₂ O (40 mL) was added and the aqueous mixture was extracted (CH ₂ Cl ₂ , 10 mL). The organic extract was washed with aqueous NaOH solution (1 M, 20 mL), brine (10 mL), dried (DDL ₄ ), filtered and concentrated in vacuo. Chromatography of silica gel (30% EtOAc in light petroleum ether) gave the title compound 16 (850 mg, 3.8 mmol, 94% in two steps) as a colorless solid. Melting point 70-71 ° C (Reference ^117-73 ° C); IR (neat method) ν _max 3422, 3050, 2956, 2236, 1705, 1418, 802 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.17 (d, J = 8.3 Hz, 1H, 8-CH), 7.91 (d, J = 7.6 Hz, 1H, 2-CH), 7.75 (d, J = 7.6 Hz, 1H, 4-CH) ), 7.61 to 7.42 (m, 4H, ArH), 4.17 (s, 2H, CH ₂ CN), 3.78 (br t, J = 5.0, 2H, NCH ₂ CH ₂ OH), 3.54 (t, J = 5.0 Hz) , 2H, NCH ₂ CH ₂ OH); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 145.8, 134.8, 129.7, 128.5, 126.2, 126.1, 125.8, 125.7, 122.9, 119.1, 116.0, 61.1, 55.1, 44.7.

1- (Naphthalene-1-yl) Azetidine-2-Carbonitrile 17:

For the production of aromatic azetidine, follow the procedure of Couty et al. ¹ . 2-[(2-Hydroxyethyl) (naphthalene-1-yl) amino] acetonitrile 16 (500 mg, 2.2 mmol) and Et ₃ N (0.77 mL, 5.5 mmol) in CH ₂ Cl ₂ solution (10 mL). MsCl (0.21 mL, 2.6 mmol) was added dropwise at 0 ° C. The colorless reaction solution was stirred at 0 ° C. for 30 minutes and gradually warmed to room temperature. The reaction was stirred at room temperature for an additional 30 minutes. H ₂ O (20 mL) was added and the organic layer was separated to extract the aqueous layer (CH ₂ Cl ₂ , 20 mL). The mixed extract was washed with aqueous HCl (2 M, 10 mL) and brine (10 mL), then dried (DDL ₄ ), filtered and concentrated in vacuo. The pale yellow residue was directly subjected to the next step and obtained in anhydrous THF (15 mL). To this solution was added ^t BuOK (297 mg, 2.6 mol) at 0 ° C. The reaction was gradually warmed to room temperature and H ₂ O (20 mL) was added. The solution was extracted (EtOAc, 3 x 20 mL), the mixed organic was washed with brine (20 mL), dried (DDL ₄ ), filtered and concentrated in vacuo. Chromatography of silica gel (10% EtOAc in light petroleum ether) gave the title compound 17 (850 mg, 3.8 mmol, 94% in two steps) as a colorless solid. Melting point 129 to 131 ° C (Reference ¹ 130 to 131 ° C); IR (neat method) ν _max 3433, 3045, 2958, 2248, 1577, 788 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ ( ppm) 7.96 to 7.82 (m, 2H, ArH), 7.56 to 7.38 (m, 4H, ArH), 6.75 (d, J = 7.3 Hz, 1H, 2-CH), 4.93 (dd, J = 8.3, 6.6 Hz) , 1H, NCH ₂ CH ₂ CHCN), 4.51 (ddd, J = 8.3, 6.6, 4.9 Hz, 1H, NCHHCH ₂ CHCN), 3.88 (dt, J = 8.3, 6.8 Hz, 1H, NCHHCH ₂ CHCN), 2.91 ~ 2.80 (m, 1H, 2H, NCH ₂ CHHCHCN), 2.78 to 2.66 (m, 1H, NCH ₂ CHHCHCN); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 145.0, 134.7, 128.6, 126.1, 125.6, 125.2, 125.1, 122.9, 122.5, 118.4, 109.5, 54.3, 51.0, 22.7.

N- (3-Butin-1-yl) Naphthylamine 18:

For the production of aromatic homopropargylamines from aromatic azetidine, follow the procedure of Couty et al. ¹ . Dibutyltin oxide (298 mg, 1.2 mmol) and TMSN ₃ (0.95 mL, 7.2 mmol) in a toluene solution (15 mL) of 1- (naphthalene-1-yl) azetidine-2-carbonitrile 17 (1.00 g, 4.8 mmol). ) Was added, and the reaction was stirred at 60 ° C. for 96 hours. The brown reaction solution was cooled to room temperature and concentrated in vacuo. Chromatography of silica gel (2% EtOAc in hexanes) gave the title compound 18 (454 mg, 2.3 mmol, 48%) as a colorless oil. IR (neat method) ν _max 3293, 3050, 2975, 2117, 1690, 767 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.90-7.79 (m, 2H, 5-CH, 8- CH), 7.57-7.29 (m, 4H, 3-CH, 4-CH, 6-CH, 7-CH), 6.66 (d, J = 7.3 Hz, 1H, 2-CH), 3.50 (t, J = 6.5 Hz, 2H, NHCH ₂ CH ₂ CCH), 2.69 (td, J = 6.5, 2.7 Hz, 2H, NHCH ₂ CH ₂ CCH), 2.11 (t, J = 2.7, 1H, NHCH ₂ CH ₂ CCH); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 146.7, 134.4, 128.7, 126.4, 125.9, 125.0, 123.8, 121.0, 119.9, 118.3, 85.2, 70.4, 27.4, 18.9.

N- (4- {6-[(hydroxyimino) methyl] pyridin-2-yl} buta-3-in-1-yl) naphthalene-1-amine 19:

Pd (PPh ₃ ) ₄ (238 mg, 0.2) in degassed anhydrous THF / Et ₃ N solution (7 mL / 3 mL) of N- (3-butin-1-yl) naphthylamine 18 (400 mg, 2.0 mmol). mmol) and CuI (78 mg, 0.4 mmol) were added. A degassed anhydrous THF solution (20 mL) of 6-bromopicoline aldehyde oxime 2 (453 mg, 2.2 mmol) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo. Chromatography of silica gel (from hexane to 10% EtOAc in hexanes) gave the title compound 19 (350 mg, 54%) as an orange solid. Melting point 143-144 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.28 (s, 1H, NOH), 7.95-7.73 (m, 4H, ArH), 7.67 (t, J = 7.8 Hz, 1H) , 3-CH), 7.53-7.33 (m, 4H, ArH), 6.70 (d, J = 7.8 Hz, 1H, 2-CH), 3.66 (t, J = 6.7 Hz, 2H, NHCH ₂ CH ₂ ), 2.96 (t, J = 6.7 Hz, 2H, NHCH ₂ CH ₂ ); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 152.0, 150.5, 143.1, 142.1, 136.8, 134.4, 128.7, 127.8, 127.3, 126.4 , 125.9, 125.0, 123.8, 120.0, 119.8, 105.2, 88.6, 81.4, 42.6, 19.8; IR (neat method) v 3350, 3152, 3047, 2864, 2645, 2200 cm ^-1 ; HRMS (ESI) ⁺ C ₂₀ H The m / z calculated value of ₁₈ N ₃ O ⁺ is 316.1444, and the measured value is 316.1445.

N- (4- {6-[(hydroxyimino) methyl] pyridin-2-yl} buta-3-in-1-yl) naphthalene-1-amine 20:

Desorption of N- (4- {6-[(1E)-(hydroxyimino) methyl] pyridin-2-yl} buta-3-in-1-yl) naphthalene-1-amine 19 (173 mg, 0.5 mmol) A Pearlman catalyst (77 mg, 0.5 mmol) was added to the air-anhydrous methanol suspension (10 mL). The reaction vessel was exhausted and washed with hydrogen gas 5 times. The black reaction mixture was stirred at room temperature for 18 hours. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo. Chromatography of silica gel (50% EtOAc in hexanes) gave the title compound 20 (60 mg, 34%) as a colorless solid. Melting point 151-152 ° C; IR (neat method) ν _max 3351, 3047, 2867, 2642 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.21 (s, 1H, NOH), 7.77- 7.67 (m, 2H, ArH), 7.60-7.49 (m, 2H, ArH), 7.41-7.30 (m, 2H, ArH), 7.26 (t, J = 8.2 Hz, 1H, NCCHCHCH), 7.15 (d, J) = 8.2 Hz, 1H, NCCHCHCH), 7.09 (dd, J = 7.1, 1.7 Hz, 1H, 7-CH), 6.53 (d, J = 7.5 Hz, 1H, 2-CH), 3.26 (t, J = 6.9) Hz, 2H, NHCH ₂ CH ₂ CH ₂ CH ₂ ), 2.85 (t, J = 6.7 Hz, 2H, NHCH ₂ CH ₂ CH ₂ CH ₂ ), 2.00 to 1.65 (m, 4H, NHCH ₂ CH ₂ CH ₂ CH) ₂ ); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 162.0, 151.1, 151.0, 143.4, 137.1, 134.3, 128.6, 126.6, 125.7, 124.7, 123.4, 123.3, 119.9, 118.6, 117.3, 104.4, 44.1 , 37.7, 28.8, 27.6; HRMS (ESI) ⁺ C ₂₀ H ₂₂ N ₃ O ⁺ m / z calculated value is 320.1757, measured value is 320.1759.
References:
1. 1. Couty et al. J. Org. Chem. 2016, 81, 2899-2910
2. 2. Couty et al. Chem. Comms. 2016, 52, 10072-10075

Synthesis of 3-hydroxy-6- (4- (quinoline-4-ylamino) butyl) methyl picolinate 26:

4-Bromoquinoline 22:

For the synthesis of bromoquinoline, follow the procedure of Margolis et al. ¹ . PBr ₃ (3.34 mL, 35.5 mmol) was added dropwise at 60 ° C. to a DMF solution (50 mL) of 4-quinolinol 21 (5.00 g, 34.4 mmol). Upon addition, a change from yellow to bright orange was observed with foaming. The orange reaction mixture was stirred at 45 ° C. for 45 minutes. The solution was cooled to room temperature, diluted with H ₂ O (20 mL), and a saturated aqueous solution of NaHCO ₃ was added slowly to base the reaction mixture to pH 10. The solution was extracted with CH ₂ Cl ₂ (5 x 20 mL), then the organic solution was mixed with H ₂ O (20 mL), washed, dried (DDL ₄ ), filtered and concentrated in vacuo. .. Silica gel chromatography (EtOAc) gave the title compound 22 (5.56 g, 26.7 mmol, 78%) as a creamy solid. Physical and spectroscopic data are in agreement with reported values ² . Melting point 28-29 ° C (Reference ² 29.5-30.5 ° C); IR (neat method) v 3062, 1615, 1058 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68 (d, J = 4.6 Hz) , 1H, NCH), 8.20 (dd, J = 8.4, 0.9 Hz, 1H, NCCHCHCHCH), 8.11 (d, J = 8.4 Hz, 1H, NCCHCHCHCH), 7.78 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H) , NCCHCH), 7.71 (d, J = 4.6 Hz, 1H, NCHCH), 7.66 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H, NCCHCHCHCH); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 149.9, 149.0 , 134.2, 130.4, 129.9, 127.9, 127.9, 126.8, 125.1.

N- (Pig-3-in-1-yl) Quinoline-4-amine 24:

For the synthesis of alkylated quinolines, follow the procedure of Musonda et al. ³ . Commercially available 3-butin-1-amine 23 (4.72 mL, 57.7 mmol) was added to 4-bromoquinoline 22 (3.00 g, 14.4 mmol) to form a light cream paste. The paste was heated at 80 ° C. for 1 hour without stirring. The temperature was raised to 140 ° C. and the paste was heated for 18 hours with stirring. The viscous brown reaction mixture is cooled to room temperature and purified by chromatography on silica gel (20% MeOH in EtOAc) to give the title compound 24 (2.82 g, 14.4 mmol, 100%) a creamy solid. Got as. Melting point 165 to 166 ° C; IR (neat method) ν _max 3281, 3169, 3067, 1573, 1151 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (d, J = 5.9 Hz, 1H) , NCH), 8.30 (dd, J = 8.3, 1.2 Hz, 1H, NCCHCHCHCH), 7.93 (br. S, 1H, NH), 7.82 (dd, J = 8.3, 1.2 Hz, 1H, NCCHCHCHCH), 7.71 (ddd) , J = 8.3, 7.0, 1.2 Hz, 1H, NCCHCHCH), 7.51 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H, NCCHCHCHCH), 6.63 (d, J = 5.9 Hz, 1H, NCHCH), 3.54 (q) , J = 7.0 Hz, 2H, NHCH ₂ CH ₂ CCH), 2.91 (t, J = 2.7 Hz, 1H, NHCH ₂ CH ₂ CCH), 2.58 (td, J = 6.8, 2.7 Hz, 2H, NHCH ₂ CH ₂ ) CCH); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 151.3, 148.2, 145.1, 130.2, 126.4, 124.7, 122.1, 118.1, 98.3, 82.1, 72.6, 41.4, 17.8; HRMS (ESI) ⁺ C ₁₃ H The m / z calculated value of ₁₃ N ₂ ⁺ is 197.173, and the measured value is 197.1072.

6- (4- (quinoline-4-ylamino) pig-1-in-1-yl) picoline aldehyde oxime 25:

Pd (PPh ₃ ) ₄ in a degassed anhydrous THF / Et ₃ N (50 mL / 15 mL) solution of N- (but-3-in-1-yl) quinoline-4-amine 24 (1.00 g, 5.1 mmol). (588 mg, 0.5 mmol) and CuI (194 mg, 1.0 mmol) were added. A degassed anhydrous THF solution (20 mL) of 6-bromopicoline aldehyde oxime 2 (1.13 g, 5.6 mmol) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. Chromatography of silica gel (20% MeOH in EtOAc) gave the title compound 25 (1.55 g, 4.9 mmol, 96%) as an orange solid. Melting point 202-203 ° C (after decomposition); IR (neat method) νmax 3291, 3068, 2947, 2241, 1617, 1222, 1051 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.90-11.69 (M, 1H, CHNOH), 8.43 (br d, J = 5.4 Hz, 1H, NCH), 8.23 (d, J = 8.3 Hz, 1H, NCCH), 8.03 (s, 1H, CHNOH), 7.85-7.65 ( m, 4H, ArH), 7.52-7.38 (m, 3H, ArH), 6.60 (d, J = 5.4 Hz, 1H, NCHCH, 3.61 (q, J = 6.7 Hz, 2H, NHCH ₂ CH ₂ ), 2.88 ( t, J = 6.7 Hz, 2H, NHCH ₂ CH ₂ ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 152.5, 150.3, 149.8, 148.4, 147.8, 142.4, 137.8, 129.0, 128.6, 126.8, 124.1, 121.7, 118.9, 118.7, 98.5, 88.7, 81.1, 48.6, 18.6; HRMS (ESI) ⁺ C ₁₉ H ₁₇ N ₄ O ⁺ m / z calculated value is 317.1397, actual measurement value is 317.1396.

Methyl 3-hydroxy-6- (4- (quinoline-4-ylamino) butyl) picolinate 26:

(E) -6- (4- (quinoline-4-ylamino) porcine-1-in-1-yl) picoline aldehyde oxime 25 (575 mg, 1.8 mmol) in a degassed anhydrous methanol suspension (20 mL). , Pearlman catalyst (255 mg, 1.8 mmol) was added. The reaction vessel was exhausted and washed with hydrogen gas 5 times. The black reaction mixture was stirred at room temperature for 18 hours. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo to give the title compound 26 (550 mg, 1.7 mmol, 94%) as a creamy solid. Melting point 218 to 219 ° C; IR (neat method) ν _max 3145, 3026, 2985, 1593, 1224, 1026, 658 cm ^-1 ; ¹ H NMR (400 MHz, D ₂ O) δ 8.15 (s, 1H, CHNOH) , 8.01 (d, J = 7.1 Hz, 1H, NCH), 7.89-7.49 (m, 7H, ArH), 6.62 (d, J = 7.1 Hz, 1H, NCHCH), 3.54 (t, J = 6.6 Hz, 2H) , NHCH ₂ CH ₂ CH ₂ CH ₂ ), 3.09 (t, J = 7.2 Hz, 2H, NHCH ₂ CH ₂ CH ₂ CH ₂ ), 1.99 to 1.76 (m, 4H, NHCH ₂ CH ₂ CH ₂ CH ₂ ); ¹³ C NMR (100 MHz, D ₂ O) δ 156.1, 146.7, 145.0, 142.7, 141.7, 137.6, 134.1, 127.5, 127.4, 123.2, 122.3, 122.1, 120.2, 116.8, 98.2, 42.9, 33.1, 26.1, 17.2; The m / z calculated value of HRMS (ESI) ⁺ C ₁₉ H ₂₁ N ₄ O ⁺ is 321.1710, and the measured value is 3321.1713.
References:
1. 1. Margolis, BJ et al. J. Org. Chem. 2007, 72, 2232-2235
2. 2. Charette, AB, et al. J. Org. Chem. 2017, 82, 5046-5067
3. 3. Musonda, C. C et al. Bioorg. Med. Chem. Lett. 2007, 17, 4733-4736

Synthesis of 6- (4-((5-fluoroquinoline-4-yl) amino) butyl) picoline aldehyde oxime 31:

4-Bromo-5-fluoroquinoline 28:

Follow the procedure of Kilpin Guy et al. ¹ for the synthesis of substituted quinoline from aniline and the procedure of Pulley et al. ² for the synthesis of quinolinol bromoquinoline. Meldrum's acid (9.49 g, 65.9 mmol) and triethyl orthoformate (21.3 mL, 128.0 mmol) were added to an EtOH solution (100 mL) of m-fluoroaniline 27 (6.00 g, 54.0 mmol) at room temperature. The yellow solution was stirred at 90 ° C. for 2.5 hours. The solution was cooled to 0 ° C., the resulting yellow solid was filtered and washed with cold EtOH (20 mL). The resulting pale yellow solid was dried and slowly added to reflux diphenyl ether (50 mL) at 280 ° C. over 5 minutes. Upon addition, a large amount of white gas was observed and the colorless solution turned orange / brown. Reflux was maintained for 5 minutes and the reaction mixture was cooled to room temperature. During this time, the solution turned much darker brown. Petroleum ether (50 mL) was added to this solution and the resulting brown growth crystals were separated by filtration. Inseparable mixture of 5-fluoroquinoline-4-ol and 7-fluoroquinoline-4-ol by silica gel chromatography (10% MeOH in EtOAc) (about 9: 1, 7.76 according to ¹⁹ F NMR). g, 47.5 mmol) was obtained. This mixture was provided directly to the next step.

Phosphorus tribromide (1.86 mL) in a DMF solution (30 mL) of an inseparable mixture of position isomers of 5-fluoroquinoline-4-ol and 7-fluoroquinoline-4-ol (4.00 g, 24.5 mmol). , 19.7 mmol) was added at 60 ° C. and the mixture was stirred at 45 ° C. for 45 minutes. After cooling to room temperature, H ₂ O (25 mL) was added, and a saturated aqueous solution of Na ₂ CO ₃ was added to adjust the pH of the solution to 10. The obtained crystals were washed with H ₂ O (10 mL). Chromatography of silica gel (25% EtOAc in hexanes) gave only 4-bromo-5-fluoroquinoline 28 (2.50 g, 11.1 mmol, 61% in 3 steps) as an orange solid. Melting point 89-90 ° C; IR (neat method) v 3091, 3041, 1621 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.67 (d, J = 4.6 Hz, 1H, NCH), 8.22 (dd) , J = 9.2, 5.9 Hz, 1H, NCCH), 7.75 (dd, J = 9.2, 2.7 Hz, 1H, NCCHCHCH), 7.68 (d, J = 4.6 Hz, 1H, NCHCH), 7.44 (ddd, J = 9.2) , 5.9, 2.7 Hz, 1H, NCCHCH); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 161.9, 150.6, 149.6, 133.7, 128.9, 124.7, 124.1, 118.0, 113.1; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ 108.7; HRMS (ESI) ⁺ C ₉ H ₆ BrFN ⁺ m / z calculated value is 225.9662, actual measurement value is 225.9658.

N- (Pig-3-in-1-yl) -5-fluoroquinoline-4-amine 29:

For the synthesis of alkylated quinolines, follow the procedure of Musonda et al. ³ . 3-Butin-1-amine 23 (0.55 mL, 6.6 mmol) was added to 4-bromo-5-fluoroquinoline 28 (1.50 g, 6.6 mmol) to produce a light orange paste. The paste was heated to 100 ° C. for 18 hours with stirring. The reaction was heated to 120 ° C. for an additional 2 hours. The viscous brown reaction mixture is cooled to room temperature and purified by chromatography on silica gel (up to 100% EtOAc in EtOAc to 20% MeOH) and the title compound 29 (1.06 g, 4.9 mmol, 75%). Was obtained as a creamy solid. Melting point 225 to 226 ° C; IR (neat method) ν _max 3079, 2911, 2240, 1966 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (d, J = 5.4 Hz, 1H, NCH ), 8.27 (dd, J = 10.8, 8.3 Hz, 1H, NCCH), 7.47 (dd, J = 10.8, 2.5 Hz, 1H, NCCHCHCH), 7.44-7.39 (m, 1H, NHCH ₂ CH ₂ CCH), 7.35 (Ddd, J = 10.8, 8.3, 2.5 Hz, 1H, NCCHCHCH), 6.49 (d, J = 5.4 Hz, 1H, NCHCH), 3.45 (q, J = 7.1 Hz, 2H, NHCH ₂ CH ₂ CCH), 2.88 (T, J = 2.7 Hz, 1H, NHCH ₂ CH ₂ CCH), 2.55 (td, J = 7.1, 2.7 Hz, 2H, NHCH ₂ CH ₂ CCH); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 163.4, 160.9, 151.9, 149.7, 124.5, 115.8, 113.5, 112.2, 98.2, 82.2, 72.4, 41.2, 17.7; ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ 112.1; HRMS (ESI) ⁺ C ₁₃ H ₁₂ The m / z calculated value of FN ₂ ⁺ is 215.0979, and the measured value is 215.0983 Da.

6-(4-((5-Fluoroquinoline-4-yl) amino) buta-1-in-1-yl) picoline aldehyde oxime 30:

Pd in a degassed anhydrous THF / Et ₃ N (7 mL / 3 mL) solution of N- (but-3-in-1-yl) -5-fluoroquinoline-4-amine 29 (0.50 g, 2.3 mmol). (PPh ₃ ) ₄ (270 mg, 0.2 mmol) and CuI (89 mg, 0.4 mmol) were added. A degassed anhydrous THF solution (20 mL) of 6-bromopicoline aldehyde oxime 2 (516 mg, 2.6 mmol) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo. Silica gel chromatography (EtOAc) gave the title compound 30 (140 mg, 0.4 mmol, 18%) as a pale cream solid. Melting point 168-169 ° C; IR (neat method) ν _max 3500, 3435, 3034, 2960, 2239, 1966, 1599, 991 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.79 (s, 1H) , CHNOH), 8.42 (d, J = 5.4 Hz, 1H, NCHCH), 8.30 (dd, J = 9.2, 7.1 Hz, 1H, NCCHCHCHCF), 8.02 (s, 1H, CHNOH), 7.83-7.69 (m, 2H) , ArH), 7.53 (t, J = 5.6 Hz, 1H, NHCH ₂ CH ₂ ), 7.48 (dd, J = 10.8, 2.7 Hz, 1H, NCCHCHCH), 7.41 (d, J = 7.1 Hz, 1H, NCCHCHCHCF) , 7.35 (td, J = 8.7, 2.7 Hz, 1H, NCCHCHCH), 6.58 (d, J = 5.4 Hz, 1H, NCHCH), 3.66 to 3.51 (m, 2H, NHCH ₂ CH ₂ ), 2.86 (t, J) = 7.0 Hz, 2H, NHCH ₂ CH ₂ ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 163.4, 160.9, 152.4, 151.9, 149.8, 148.4, 142.4, 137.3, 126.9, 124.5, 119.0, 115.9, 113.5 , 112.2, 98.4, 88.7, 81.1, 41.0, 18.6; ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ 111.9; HRMS (ESI) ⁺ C ₁₉ H ₁₆ FN ₄ O ⁺ m / z calculated value is 335.1303, The measured value is 335.1298.

6-(4-((5-Fluoroquinoline-4-yl) amino) butyl) picoline aldehyde oxime 31:

6- (4-((5-Fluoroquinoline-4-yl) amino) buta-1-in-1-yl) picoline aldehyde oxime 30 (50 mg, 0.1 mmol) degassed anhydrous methanol suspension (5 mL) ), A Pearlman catalyst (21 mg, 0.1 mmol) was added. The reaction vessel was exhausted and washed with hydrogen gas 5 times. The black reaction mixture was stirred at room temperature for 18 hours. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo to give the title compound 31 (50 mg, 0.1 mmol, 99%) as a creamy solid. Melting point 206-207 ° C; IR (neat method) v _max 3247, 2935, 2859, 1978, 1584, 806 cm ^-1 ; ¹ H NMR (400 MHz, D ₂ O) δ 8.44 (t, J = 8.1 Hz, 1 H) , NCCHCHCH), 8.19 (d, J = 7.3 Hz, 1H, NCHCH), 8.16 to 8.13 (m, 2H, CHNOH, NHCH ₂ CH ₂ CH ₂ CH ₂ ), 7.91 to 7.81 (m, 2H, NCCHCHCHCF, NCCHCHCHCF) , 7.70 (d, J = 8.1 Hz, 1H, NCCHCHCH), 7.42-7.32 (m, 2H, NCCHCHCH), 6.70 (d, J = 7.3 Hz, NCHCH), 3.58 (t, J = 6.8 Hz, 2H, NHCH) ₂ CH ₂ CH ₂ CH ₂ ), 3.12 (t, J = 7.7 Hz, 2H, NHCH ₂ CH ₂ CH ₂ CH ₂ ), 2.01 to 1.76 (m, 4H, NHCH ₂ CH ₂ CH ₂ CH ₂ ); ¹³ C NMR (100 MHz, D ₂ O) δ 166.0, 136.5, 161.5, 159.1, 155.8, 146.5, 141.9, 139.0, 127.0, 125.6, 124.0, 116.2, 113.5, 105.1, 98.0, 42.8, 39.9, 26.9, 25.9; ¹⁹ F NMR (376 MHz, D ₂ O) δ 103.1; HRMS (ESI) ⁺ C ₁₉ H ₂₂ FN ₄ O ⁺ m / z calculated value is 339.1980, measured value is 339.1980.
References:
1. 1. Kiplin Guy, R. et al. Bioorg. Med. Chem. Lett. 2005, 15, 1015-1018
2. 2. Pulley et al. J. Org. Chem. 2007, 72, 2232-2235
3. 3. Musonda, CC et al. Bioorg. Med. Chem. Lett. 2007, 17, 4733-4736

Synthesis of 6- (4-((8-methoxyquinoline-4-yl) amino) butyl) picoline aldehyde oxime 37:

8-Methoxyquinoline-4-all 33:

For the synthesis of substituted quinoline from aniline, follow the procedure of Kilpin Guy et al. ¹ . Meldrum's acid (3.57 g, 24.8 mmol) and triethyl orthoformate (8.00 mL, 48.0 mmol) were added to an EtOH solution (20 mL) of o-anisidine 32 (2.50 g, 20.3 mmol) at room temperature. The yellow solution was stirred at 90 ° C. for 2.5 hours. The solution was cooled to 0 ° C., the resulting yellow solid was filtered and washed with cold EtOH (20 mL). The resulting pale yellow solid was dried and slowly added to reflux diphenyl ether (50 mL) at 280 ° C. over 5 minutes. Upon addition, a large amount of white gas was observed and the colorless solution turned orange / brown. Reflux was maintained for 5 minutes and the reaction mixture was cooled to room temperature. During this time, the solution turned much darker brown. Petroleum ether (50 mL) was added to this solution and the resulting yellow growth crystals were separated by filtration. Chromatography of silica gel (5% MeOH in EtOAc) gave 8-methoxyquinoline-4-ol 33 (7.76 g, 47.5 mmol) as a pale orange solid. Melting point 168 ° C (Reference ² : 168 to 169 ° C); IR (neat method) v 2921, 2851, 1272, 1041 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 11.35 (s, 1H, OH), 7.58-7.70 (m, 1H, NCH), 7.38-7.43 (m, 1H, ArH), 7.23-7.27 (m, 2H, OHCCCH, OMeCCH), 6.95-7.08 (m, 1H, OHCCH) , 3.99 (s, 3H, OMe); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm) 177.1, 149.0, 139.3, 130.5, 123.2, 119.1, 116.7, 111.4, 109.6, 56.6; HRMS (ESI) The m / z calculated value of ⁺ C ₁₀ H ₁₀ NO ₂ ⁺ is 176.0706, and the measured value is 176.0707.

4-Bromo-8-methoxyquinoline 34:

For the synthesis of bromoquinoline from quinolinol, follow the procedure of Pulley et al. ³ . To a DMF solution (20 mL) of 8-methoxyquinoline-4-ol 33 (2.50 g, 14.3 mmol) is added phosphorus tribromide (1.54 mL, 16.4 mmol) at 60 ° C, and the mixture is added to the mixture at 45 ° C for 45 minutes. Stirred. After cooling to room temperature, H ₂ O (25 mL) was added, and a saturated aqueous solution of Na ₂ CO ₃ was added to adjust the pH of the solution to 10. The resulting cream-colored crystals were filtered and washed with H ₂ O (10 mL) to give 4-bromo-5-fluoroquinoline 34 (2.58 g, 10.8 mmol, 76%) as a creamy solid. Melting point 99-101 ° C; IR (neat method) ν _max 1252, 1085 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.69 (d, J = 4.6 Hz, 1H, NCH), 7.78 (D, J = 8.1 Hz, 1H, BrCCCH), 7.75 (d, J = 4.8 Hz, 1H, BrCCH), 7.58 (t, J = 8.2 Hz, 1H, ArH), 7.14 (d, J = 8.0 Hz, 1H, ArH), 4.12 (s, 3H, OMe); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 155.5, 148.5, 134.1, 129.0, 128.0, 125.8, 118.5, 108.5, 56.3; HRMS (ESI) The m / z calculated value of ⁺ C ₁₀ H ₉ BrNO ⁺ is 237.9862, and the measured value is 237.9865.

N- (Pig-3-in-1-yl) -8-methoxyquinoline-4-amine 35:

For the synthesis of alkylated quinolines, follow the procedure of Musonda et al. ⁴ . 3-Butin-1-amine 23 (1.20 mL, 14.7 mmol) was added to 4-bromo-8-methoxyquinoline 34 (0.70 g, 2.9 mmol) to produce an orange / yellow paste. The paste was heated to 80 ° C. for 1 hour without stirring. The temperature was raised to 100 ° C. for 18 hours with stirring. The viscous brown reaction mixture is cooled to room temperature and purified by chromatography of alumina (basic) gel (10% MeOH in EtOAc) to give the title compound 35 (0.80 g, 2.9 mmol, 99%). Obtained as a pale orange solid. Melting point 154 to 155 ° C; IR (neat method) ν _max 3279, 2938, 2240, 753 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 8.36 (d, J = 5.4 Hz, 1H, NCH), 7.73 (d, J = 7.8 Hz, 1H, MeOCCHCHCH), 7.35 (t, J = 8.1 Hz, 1H, MeOCCHCH), 7.10 (d, J = 7.3 Hz, 1H, OMeCCH), 6.55 (d) , J = 5.4 Hz, 1H, NCHCH), 3.91 (s, 3H, OMe), 3.39 to 3.53 (m, 2H, CH ₂ CH ₂ CCH), 2.89 (t, J = 2.6 Hz, 1H, CH ₂ CH ₂ ) CCH), 2.56 (td, J = 7.1, 2.7 Hz, 2H, CH ₂ CH ₂ CCH); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm) 155.2, 149.9, 148.8, 139.6, 124.3, 119.6 , 113.3, 108.5, 99.1, 82.5, 72.6, 55.8, 41.5, 18.0; HRMS (ESI) ⁺ C ₁₄ H ₁₅ N ₂ O ⁺ m / z calculated value is 227.1179, measured value is 227.1183.

6- (4-((8-Methoxyquinoline-4-yl) amino) buta-1-in-1-yl) picoline aldehyde oxime 36:

Pd in a degassed anhydrous THF / Et ₃ N (7 mL / 3 mL) solution of N- (but-3-in-1-yl) -8-methoxyquinoline-4-amine 35 (1.00 g, 4.4 mmol). (PPh ₃ ) ₄ (511 mg, 0.4 mmol) and CuI (168 mg, 0.9 mmol) were added. A degassed anhydrous THF solution (20 mL) of 6-bromopicoline aldehyde oxime 2 (977 mg, 4.8 mmol) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo. Chromatography of the alumina (basic) gel (10% MeOH in EtOAc) gave the title compound 36 (400 mg, 1.1 mmol, 26%) as a yellow solid. Melting point 171-172 ° C; IR (neat method) ν _max 3084, 2900, 2236, 1617, 1277, 745 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.79 (s, 1H, CHNOH), 8.35 (d, J = 6.1 Hz, 1H, NCHCH), 7.98 (m, 2H, NCC (OMe) CHCHCH, CHNOH), 7.78 (t, J = 7.8 Hz, 1H, NCCHCHCH), 7.72 (d, J = 7.8) Hz, 1H, NCCHCHCH), 7.49 (d, J = 8.2 Hz, 1H, NCC (OMe) CHCHCH), 7.39 (d, J = 7.8 Hz, 1H, NCCHCHCH), 7.29 (d, J = 8.2 Hz, 1H, NCC (OMe) CHCHCH), 6.84 (d, J = 6.1 Hz, 1H, NCHCH), 3.99 (s, 3H, OMe), 3.71 (br t, J = 7.0, 2H, NHCH ₂ CH ₂ ), 2.90 (t) , J = 7.0 Hz, 2H, NHCH ₂ CH ₂ ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 152.6, 152.5, 152.1, 148.3, 145.1, 142.3, 137.3, 134.2, 126.8, 125.4, 119.0, 118.5 , 113.7, 110.3, 99.0, 88.3, 81.3, 56.1, 48.5, 18.7; HRMS (ESI) ⁺ C ₂₀ H ₁₉ N ₄ O ₂ ⁺ m / z calculated value is 347.1503, measured value is 347.1506.

6-(4-((8-Methoxyquinoline-4-yl) amino) butyl) picoline aldehyde oxime 37:

6- (4-((8-Methoxyquinoline-4-yl) amino) buta-1-in-1-yl) picoline-aldehyde oxime 36 (110 mg, 0.3 mmol) degassed anhydrous methanol suspension (10) To (mL) was added a Pearlman catalyst (9 mg, 0.1 mmol). The reaction vessel was exhausted and washed with hydrogen gas 5 times. The black reaction mixture was stirred at room temperature for 18 hours. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo to give the title compound 37 (40 mg, 0.1 mmol, 36%) as a creamy solid. Melting point 107-108 ° C; IR (neat method) ν _max 2927, 1617, 1581, 980 cm ^-1 ; ¹ H NMR (400 MHz, MeOD-d ₆ ) δ 8.29 (d, J = 5.6 Hz, 1H, NCHCH) , 8.08 (s, 1H, CHNOH), 7.71 to 7.57 (m, 3H, ArH), 7.34 (t, J = 8.2 Hz, 1H, NCC (OMe) CHCHCH), 7.24 to 7.19 (m, 1H, NCC (OMe) ) CHCHCH), 7.08 (d, J = 7.8 Hz, 1H, NCCHCHCH), 6.48 (d, J = 5.6 Hz, NCHCH), 3.98 (s, 3H, OMe), 3.36 (t, J = 7.1 Hz, 2H, NHCH ₂ CH ₂ CH ₂ CH ₂ ), 2.83 (t, J = 7.1 Hz, 2H, NHCH ₂ CH ₂ CH ₂ CH ₂ ), 1.94 to 1.66 (m, 4H, NHCH ₂ CH ₂ CH ₂ CH ₂ ); ¹³ C NMR (100 MHz, MeOD-d ₆ ) δ 163.2, 156.2, 153.3, 152.7, 150.0, 149.6, 140.4, 138.8, 125.8, 124.5, 121.1, 119.3, 113.8, 109.3, 99.9, 56.4, 43.8, 38.4, 28.9, 28.7: The m / z calculated value of HRMS (ESI) ⁺ C ₂₀ H ₂₃ N ₄ O ₂ ⁺ is 351.1816, and the measured value is 351.1817.
References:
2. 2. Kiplin Guy, R. et al. Bioorg. Med. Chem. Lett. 2005, 15, 1015-1018
3. 3. Lauer et al. J. Am. Chem. Soc., 1946, 68, 1268
4. Pulley et al. J. Org. Chem. 2007, 72, 2232-2235
5. Musonda, CC; Little, S .; Yardley, V .; Chibale, K. Bioorg. Med. Chem. Lett. 2007, 17, 4733-4736

Synthesis of 6- (3- (4-benzylpiperazine-1-yl) propyl) picoline aldehyde oxime 43:

N-Benzylpiperazine 39:

For the synthesis of benzylpiperazine, follow the procedure of Bozell and Biannic ¹ . Benzyl bromide (3.56 mL, 29.8 mmol) was added dropwise at 0 ° C. to an anhydrous CH ₂ Cl ₂ solution (100 mL) of piperazine 38 (12.9 g, 149.0 mmol). The reaction was stirred at 0 ° C. for 1 hour. The pale yellow solution was washed with saturated aqueous solution of NaHCO ₃ (2 x 50 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Pure EtOH was added and the white precipitate was filtered from the solution. The solution was concentrated in vacuo to give the title compound 39 (24.8 g, 141.0 mmol, 94%) as a viscous yellow oil. IR (neat method) ν _max 3289, 2990, 2960, 2120, 1120 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.36-7.28 (m, 5H, ArH), 3.50 (s, 2H) , CH ₂ Ph), 2.90 (t, J = 4.9 Hz, 4H, CH ₂ N (Bn) CH ₂ ), 2.55 to 2.30 (m, 5H, CH ₂ NHCH ₂ ); ¹³ C NMR (101 MHz, CDCl ₃ ) ) Δ (ppm) 138.1, 129.2, 128.2, 127.0, 63.7, 54.5, 46.1.

1-Benzyl-4-propargyl piperazine 41:

For piperazine propargyl replacement, follow the procedure in Corey, ^M.2 . CH ₂ Cl ₂ solution of propargyl 40 (80% in toluene) (1.28 mL, 14.9 mmol) and DIPEA (3.28 mL, 19.9 mmol) in a solution of N-benzylpiperazine 39 (1.75 g, 9.93 mmol). 50 mL) was stirred at room temperature for 18 hours. H ₂ O (30 mL) was added and the aqueous phase was separated and extracted (3 x 20 mL). The mixed organic layer was washed (brine, 30 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Chromatography of silica gel (50% EtOAc in hexanes) gave the title compound 41 (2.04 g, 9.5 mmol, 96%) as an orange oil. IR (neat method) ν _max 3290, 3026, 2933, 2807, 2117, 697 cm- ¹ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.37-7.28 (m, 5H, ArH), 3.56 (s) , 2H, PhCH ₂ ), 3.30 (d, J = 2.5 Hz, 2H, NCH ₂ CCH), 2.73 to 2.44 (m, 8H, PizCH ₂ ), 2.25 (t, J = 2.5 Hz, 1H, NCH ₂ CCH) ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 129.5, 129.3, 128.3, 127.2, 78.9, 73.20, 62.8, 52.8, 51.7, 46.8; HRMS (ESI) ⁺ C _x H _x N _x ⁺ m / z The calculated value is 215.1543 and the measured value is 215.1542.

6- (3- (4-Benzylpiperazine-1-yl) propa-1-in-1-yl) picoline aldehyde oxime 42:

Pd (PPh ₃ ) ₄ (0.70 g, 0.6 mmol) and CuI in a degassed anhydrous THF / Et ₃ N (7 mL / 3 mL) solution of 1-benzyl-4-propargylpiperazin 41 (1.30 g, 6.1 mmol). (0.23 g, 1.2 mmol) was added. A degassed anhydrous THF (20 mL) solution of 6-bromopicoline aldehyde oxime 2 (1.34 g, 6.7 mmol) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. Silica gel chromatography (EtOAc) gave the title compound 42 (750 mg, 2.2 mmol, 37%) as a creamy solid. Melting point 143-145 ° C; IR (neat method) ν _max 3150, 3048, 2944, 2808, 2364, 734 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 12.17 (s, 1H, NOH) , 7.99 (s, 1H, CHNOH), 7.71 (dd, J = 8.0, 1.0 Hz, 1H, NCCHCHCH), 7.53 (t, J = 8.0 Hz, 1H, NCCHCHCH), 7.43-7.20 (m, 6H, ArH) , 3.70 (s, 2H, NCH ₂ CC), 3.63 (s, 2H, PhCH ₂ ), 3.08-2.36 (m, 8H, PizCH ₂ ); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 152.7, 149.0, 142.2, 136.4, 136.3, 129.9, 128.4, 127.6, 127.1, 119.1, 85.3, 84.3, 63.2, 52.9, 50.5, 47.2; HRMS (ESI) ⁺ C ₂₀ H ₂₃ N ₄ O ⁺ m / z calculated value 335.1866, the measured value is 335.1863.

6- (3- (4-Benzylpiperazine-1-yl) propyl) picoline aldehyde oxime 43:

In a degassed anhydrous methanol suspension (10 mL) of 6- (3- (4-benzylpiperazine-1-yl) propa-1-in-1-yl) picoline aldehyde oxime 42 (200 mg, 0.6 mmol), Pearlman's catalyst (44 mg, 0.3 mmol) was added. The reaction vessel was exhausted and washed with hydrogen gas 5 times. The black reaction mixture was stirred at room temperature for 2 hours. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo. Silica gel chromatography (from CH ₂ Cl ₂ to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound 43 as a pale yellow oil (53%). IR (neat method) ν _max 3162, 3057, 2939, 2816, 808 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.19 (s, 1H, CHNOH), 7.58 to 7.51 (m, 2H) , ArH), 7.36-7.27 (m, 5H, ArH), 7.10 (dd, J = 6.5, 2.2 Hz, 1H, NCCHCHCH), 3.55 (s, 2H, PhCH ₂ ), 2.82 (t, J = 7.8 Hz, 1H, NCH ₂ CH ₂ CH ₂ ), 2.72 to 2.35 (m, 10H, PizCH ₂ , NCH ₂ CH ₂ CH ₂ ), 2.02 (5-fold wire ,, J = 7.8 Hz, NCH ₂ CH ₂ CH ₂ ); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 161.3, 151.8, 150.3, 137.6, 136.6, 129.4, 128.3, 127.2, 122.8, 118.0, 62.9, 57.7, 25.8, 25.5, 35.8, 26.3; HRMS (ESI) ⁺ The m / z calculated value of C ₂₀ H ₂₇ N ₄ O ⁺ is 339.2179, and the measured value is 339.2176.
References 1. Bozell. JJ et al. Org. Lett. 2013, 15, 2730-2733
2. 2. Corey, M., et al. WO2017 / 184996 A1 (2017)

Synthesis of 6- (3- (4-benzylpiperazine-1-yl) propyl) picoline aldehyde oxime 48:

3-butynyl p-toluenesulfonic acid 45:

The procedure of Winssinger et al. ¹ is followed for the production of the p-torun sulfonyl protected alcohol. 3-Butin-1-ol 44 (3.00 g, 42.8 mmol), DMAP (522 mg, 4.3 mmol) and Et ₃ N (55.6 mL, 7.70 mmol) in CH ₂ Cl ₂ solution (15 mL) at 0 ° C. A TsCl solution (8.98 g, 47.1 mmol) was added dropwise. The yellow reaction solution was warmed to room temperature and stirred for 2 hours. H ₂ O (30 mL) was added and the reaction was stirred at room temperature for 20 minutes. The organic layer was separated and the aqueous layer was extracted (CH ₂ Cl ₂ , 5 × 40 mL). The mixed extract was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. This gave the title compound 45 (9.60 g, 42.8 mmol, 100%) as a red / brown oil. IR (neat method) ν _max 3433, 3045, 2958, 2248, 1577, 788 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.81 (d, J = 8.3 Hz, 2H, ArH), 7.36 (d, J = 8.3 Hz, 2H, ArH), 4.11 (t, J = 7.1 Hz, 2H, TsOCH ₂ CH ₂ CCH), 2.56 (td, J = 7.1, 2.7 Hz, 2H, TsOCH ₂ TsOCH ₂ CH) ₂ CCH), 2.46 (s, 3H, PhCH ₃ ), 1.98 (t, J = 2.7 Hz, 1H, TsOCH ₂ CH ₂ CCH); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 145.0, 132.8, 129.9, 128.0, 78.3, 70.7, 67.4, 21.6, 19.4.

1-Benzyl-4- (Buta-3-in-1-yl) piperazine 46:

For the production of alkylated piperazine, follow the procedure of Guarna et al. ² . Na ₂ CO ₃ (1.20 g, 11.3 mmol) and N-benzylpiperazine 39 (2.00 g, 11.3 mmol) in a DMF solution (60 mL) of p-toluenesulfonic acid 3-butynyl 45 (2.30 mL, 10.3 mmol). added. The orange solution was stirred at 80 ° C. overnight. The reaction mixture was stopped at H ₂ O (10 mL) and ether (10 mL) was added. The organic layer was separated, washed with H ₂ O (5 x 10 mL), brine (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Silica gel chromatography (from 100% CH ₂ Cl ₂ to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound 46 (1.70 g, 7.4 mmol, 72%) as an orange oil. IR (neat method) ν _max 3291, 3026, 2939, 2807, 2119, 1676, 697 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.35 to 7.28 (m, 5H, ArH), 3.52 (S, 2H, PhCH ₂ ), 2.61 (t, J = 7.6 Hz, 2H, NCH ₂ CH ₂ CCH), 2.58 to 2.42 (m, 8H, PizCH ₂ ), 2.41 to 2.34 (m, 2H, NCH ₂ CH) ₂ CCH), 1.97 (t, J = 2.7 Hz, 1H, NCH ₂ CH ₂ CCH); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 138.1, 129.2, 128.2, 127.0, 82.8, 69.0, 63.0, 57.0, 52.9, 52.8, 16.8; HRMS (ESI) ⁺ CxHxNx ⁺ m / z calculated value is 229.1699, measured value is 229.1695.

6- (4- (4-Benzylpiperazine-1-yl) buta-1-in-1-yl) picoline aldehyde oxime 47:

Pd (PPh ₃ ) in a degassed anhydrous THF / Et ₃ N (7 mL / 3 mL) solution of 1-benzyl-4- (but-3-in-1-yl) piperazine 46 (1.55 g, 6.8 mmol). ₄ (1.16 g, 0.7 mmol) and CuI (0.19 g, 1.4 mmol) were added. A degassed anhydrous THF solution (20 mL) of 6-bromopicoline aldehyde oxime 2 (1.50 g, 7.47 mmol) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. Chromatography of silica gel (from 50% EtOAc to EtOAc in Hexanes) gave the title compound 47 (150 mg, 0.4 mmol, 6%) as a creamy solid. Melting point 134-136 ° C; IR (neat method) ν _max 3161, 3060, 2954, 2808, 2231, 740 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 11.48 (s, 1H, NOH) ), 8.20 (s, 1H, CHNOH), 7.76 (dd, J = 8.0, 1.0 Hz, 1H, NCCHCHCH), 7.59 (t, J = 8.0 Hz, 1H, NCCHCHCH), 7.35-7.27 (m, 6H, ArH) ), 3.56 (s, 2H, PhCH ₂ ), 2.82 to 2.41 (m, 12H, PizCH ₂ , NCH ₂ CH ₂ CC); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 152.9, 149.7, 143.1, 137.4, 136.5, 129.5, 128.3, 127.3, 126.7, 119.1, 89.1, 80.8, 63.0, 56.6, 52.6, 52.5, 17.4; HRMS (ESI) ⁺ C ₂₁ H ₂₅ N ₄ O ⁺ m / z calculated value is 349.2023, The measured value is 349.2018.
References 1. Winssinger et al. Chem. Comms. 2010, 46, 5476-5478
2. 2. Guarna et al. J. Med. Chem. 2010, 53, 7119-7128

6- (4- (4-Benzylpiperazine-1-yl) butyl) picoline aldehyde oxime 48:

In a suspension of 6- (4- (4-benzylpiperazine-1-yl) porcine-1-in-1-yl) picoline aldehyde oxime 47 (60 mg, 0.2 mmol) in degassed anhydrous methanol (5 mL), Platinum (10%, 4 mg, 0.04 mmol on the carbon surface) was added. The reaction vessel was exhausted and washed with hydrogen gas 5 times. The black reaction mixture was stirred at room temperature for 1.5 hours. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo to give the title compound 48 (53 mg, 0.2 mmol, 87%) as a yellow oil. IR (neat method) ν _max 3181, 3060, 2938, 2818, 791 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.18 (s, 1H, CHNOH), 7.62-7.50 (m, 2H) , ArH), 7.34-7.29 (m, 5H, ArH), 7.11 (dd, J = 7.3, 1.4 Hz, 1H, NCCHCHCH), 5.31 (s, 2H, PhCH ₂ ), 2.82 (t, J = 7.3 Hz, 2H, NCH ₂ CH ₂ CH ₂ CH ₂ ), 2.59 to 2.31 (m, 10H, PizCH ₂ , NCH ₂ CH ₂ CH ₂ CH ₂ ), 1.76 (5-fold wire, J = 7.3 Hz, NCH ₂ CH ₂ CH ₂ ) CH ₂ ), 1.58 (br s, 2H, NCH ₂ CH ₂ CH ₂ CH ₂ ); ¹³ C NMR (101 MHz, CDCl ₃ ) δ (ppm) 161.9, 151.5, 150.6, 136.7, 136.6, 129.3, 128.2, 127.1 , 122.9, 118.1, 63.0, 58.4, 53.0, 52.7, 37.9, 27.6, 26.1; HRMS (ESI) ⁺ C ₂₀ H ₂₇ N ₄ O ⁺ m / z calculated value is 353.2336, actual measurement value is 353.2332.

6- (4- (3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-1-yl) pig-1-in-1-yl) picoline aldehyde oxime Synthesis 51:

1- (Pig-3-in-1-yl) -3,7-dimethyl-dihydro-1H-purine-2,6-dione 50:

For the synthesis of substituted amines by the Mitsunobu reaction, follow the procedure of Ito et al. ¹ . ADDP (700 mg, 700 mg) in THF solution (15 mL) of 3-butin-1-ol 44 (0.10 mL, 1.4 mmol), theobromine 49 (500 mg, 2.8 mmol) and triphenylphosphine (728 mg, 2.8 mmol). 2.8 mmol) was added at room temperature. The yellow reactant was heated to 60 ° C. for 24 hours. The cream-colored reaction solution was diluted (H ₂ O, 50 mL) and the aqueous solution was extracted (EtOAc, 3 x 20 mL). The mixed organic layer was dried (DDL ₄ ), filtered and concentrated in vacuo. The white residue was purified by silica gel chromatography (EtOAc) to 1- (but-3-in-1-yl) -3,7-dimethyl-dihydro-1H-purine-2,6-dione 50 ( 120 mg, 0.5 mmol, 37%) was obtained as a white solid. Melting point 192 to 193 ° C; IR (neat method) ν _max 3228, 3107, 2951, 1697, 1651 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 8.00 (s, 1H, NCHN) ), 3.99 (t, J = 7.6 Hz, 2H, NCH ₂ CH ₂ CCH), 3.87 (s, 3H, NCHN (CH ₃ )), 3.40 (s, 3H, NCON (CH ₃ )), 2.84 (t, J = 2.7 Hz, 1H, NCH ₂ CH ₂ CCH), 2.45 (td, J = 7.6, 2.7 Hz, 1H, NCH ₂ CH ₂ CCH); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm) 154.6, 151.1, 148.7, 143.5, 107.0, 81.5, 73.0, 40.6, 33.6, 29.8, 17.3; HRMS (ESI) ⁺ C ₁₁ H ₁₃ N ₄ O ₂ ⁺ m / z calculated value is 233.133 and measured value is 233.1035, C ₁₁ H ₁₂ N ₄ NaO ₂ ⁺ m / z calculated value is 255.0852 and measured value is 255.0857.

6- (4- (3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-1-yl) pig-1-in-1-yl) picoline aldehyde oxime 51 :

1- (Buta-3-in-1-yl) 3,7-dimethyl-dihydro-1H-purine-2,6-dione 50 (200 mg, 0.9 mmol) degassed anhydrous THF / Et ₃ N (7 mL) To the / 3 mL) solution was added Pd (PPh ₃ ) ₄ (99 mg, 0.1 mmol) and CuI (33 mg, 0.2 mmol). A degassed anhydrous THF (10 mL) solution of 6-bromopicoline aldehyde oxime 2 (190 mg, 1.0 mmol) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo to give an orange solid as a crude product. Chromatography of silica gel (from EtOAc to 10% MeOH in EtOAc) gave the title compound 51 (111 mg, 0.3 mmol, 36%) as a colorless solid. Melting point 210-211 ℃; IR (neat method) ν _max 3178, 3087, 2872, 2230, 1700, 1647, 759 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.75 (s, 1H, CHNOH) ), 8.03 (s, 1H, CHNOH), 8.00 (s, 1H, NCHN), 7.79 (t, J = 8.1 Hz, 1H, NCCHCHCH), 7.73 (dd, J = 8.1, 1.0 Hz, 1H, NCCHCHCH), 7.39 (dd, J = 8.1, 1.0 Hz, 1H, NCCHCHCH), 4.12 (t, J = 7.5 Hz, 2H, NHCH ₂ CH ₂ ), 3.88 (s, 3H, NCHN (CH ₃ )), 3.42 (s, 3H, NCON (CH ₃ )), 2.75 (t, J = 7.5 Hz, 2H, NHCH ₂ CH ₂ ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 154.2, 152.4, 150.7, 148.4, 148.3, 143.1 , 142.3, 137.3, 126.8, 119.0, 118.9, 106.5, 87.4, 81.3, 33.2, 29.4, 17.7; HRMS (ESI) ⁺ C ₁₇ H ₁₇ N ₆ O ₃ ⁺ m / z calculated value is 353.1357, measured value is 353.1358 ..
References 1. Ito, S. et al. Tet. Letts., 1993, 34, 1639-1642

II-Synthesis of bifunctional Neca analogs

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -N- (but-3-in-1-yl) -2,2-dimethyltetrahydro-flo [3] , 4-d] [1,3] Dioxol-4-carboxamide 54:

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -2,2-dimethyltetrahydro-flo [3,4-d] [1,3] dioxol-4- The synthesis of carboxylic acid 53 was accomplished using the procedure of Debnath, J. et al. ¹ .

1-Amino-3-butin 22 (140 μL, 1.71 mmol, 1.1 eq) and EDCI (598 mg, 3.12 mmol) in a dry pyridine stirring solution (15 mL) of acid 53 (500 mg, 1.56 mmol, 1 eq). 2 eq) were added continuously and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. Upon completion, the reaction mixture is concentrated directly under reduced pressure and the residue is purified by column chromatography (from EtOAc to 95: 5 EtOAc / MeOH) to give the desired amide 54 a pale yellow solid (500 mg, 500 mg,). Obtained as 80%). R _f (pure EtOAc) 0.18; IR (neat method) ν _max 3289, 3142, 1672, 1601, 1526, 1206, 1090, 1058, 868, 789, 645, 514 cm ^-1 ; ¹ H NMR (400 MHz, 400 MHz, CDCl ₃ ) δ (ppm) 8.32 (s, 1H), 7.89 (s, 1H), 7.28 (m, 1H), 6.33 (s, 2H), 6.13 (d, J = 2.5 Hz, 1H), 5.47 (dd) , J = 2.1, 6.2 Hz, 1H), 5.39 (dd, J = 2.5, 6.2 Hz, 1H), 4.74 (d, J = 2.1 Hz, 1H), 3.21 (m, 2H), 2.21 (m, 1H) , 2.10 (m, 1H), 1.82 (t, J = 2.6 Hz, 1H), 1.63 (s, 3H), 1.40 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 168.98, 155.86, 153.11, 148.99, 139.82, 120.21, 114.37, 91.70, 86.33, 83.59, 82.88, 80.81, 69.83, 37.49, 26.95, 25.07, 18.85; HRMS (ESI) ⁺ C ₁₇ H ₂₁ N ₆ O ₄ ⁺ m / z The calculated value is 373.1575, and the measured value is 373.1619.

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -N- (4- (6-formylpyridine-2-yl) pig-3-in-1-yl) ) -2,2-Dimethyltetrahydroflo [3,4-d] [1,3] Dioxol-4-carboxamide 55:

Pd [PPh ₃ ] ₄ (233 mg, 0.202 mmol, 0.15 eq) in a degassed THF / Et ₃ N (10 mL / 8 mL) solution of methyl 6-bromopicoline aldehyde 1 (275 mg, 1.478 mmol, 1.1 eq). ) And CuI (77 mg, 0.403 mmol, 0.3 eq) were added. After degassing the reaction mixture at room temperature for 5 minutes, a degassed THF solution (10 mL) of Alkin 54 (500 mg, 1.344 mmol, 1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography (from pure EtOAc to 9: 1 EtOAc / MeOH) to the desired bound picoline aldehyde 55 in a concentrated syrup (510 mg,). Obtained as 80%). IR (neat method) ν _max 3318, 1638, 1582, 1452, 1209, 1078, 868, 797, 646, 509 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 9.90 (s, 1H) , 8.24 (s, 1H), 7.85-7.65 (m, 3H), 7.38 (m, 1H), 6.40 (s, 1H), 6.02 (s, 1H), 5.33 (s, 2H), 4.70 (s, 1H) ), 3.35 (m, 2H), 2.60 to 2.32 (m, 2H), 1.57 (s, 3H), 1.31 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 192.88, 169.13, 155.67, 153.12, 152.63, 148.97, 143.63, 139.87, 137.20, 130.85, 120.19, 114.62, 91.94, 88.87, 85.74, 83.55, 82.54, 80.66, 37.41, 27.09, 25.11, 20.08; HRMS (ESI) ⁺ C ₂₃ H ₂₄ N The m / z calculated value of ₇ O ₅ ⁺ is 478.1806, and the measured value is 478.1833.

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -N- (4- (6- (hydroxyimino) methyl) pyridin-2-yl) pig-3- In-1-yl) -2,2-Dimethyltetrahydroflo [3,4-d] [1,3] Dioxol-4-carboxamide 56:

A dry ethanol solution of picoline aldehyde 55 (80 mg, 0.168 mmol, 1 eq), hydroxylamine hydrochloride (23 mg, 0.336 mmol, 2 eq), and CH ₃ CO ₂ Na (41 mg, 0.503 mmol, 3 eq) (5). mL) was refluxed and stirred for 16 hours. After concentration under reduced pressure, the crude product was washed with CH ₂ Cl ₂ (5 * 10 mL) to remove all impurities. The compound present in the round-bottom flask was picoline aldehyde oxime 56, which was dried in high vacuum (82 mg, quantitative yield) and confirmed by ¹ H NMR. R _f (EtOAc); IR (neat method) ν _max 3186, 2925, 1643, 1579, 1207, 1089, 980, 867, 797, 726, 649, 509 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.20 (s, 1H), 8.11 (s, 1H), 7.92 (m, 2H), 7.46 (m, 2H), 7.02 (m, 3H), 6.05 (d, J = 2.7 Hz, 1H) , 5.35 (dd, J = 2.0, 6.2 Hz, 1H), 5.29 (dd, J = 2.7, 6.2 Hz, 1H), 4.74 (d, J = 2.0 Hz, 1H), 3.41 (m, 2H), 2.57 ~ 2.33 (m, 2H), 1.59 (s, 3H), 1.433 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 169.14, 155.54, 152.89, 152.05, 149.16, 148.60, 142.61, 139.82 , 136.66, 126.72, 119.58, 119.47, 114.74, 91.86, 88.15, 85.78, 83.45, 82.68, 81.13 37.45, 27.11, 25.14, 20.21; HRMS (ESI) ⁺ C ₂₃ H ₂₅ N ₈ O ₅ ⁺ m / z calculated value Is 493.1901, and the measured value is 493.1942.

(2S, 3S, 4R, 5R) -5- (6-amino-9H-purine-9-yl) -3,4-dihydroxy-N- (4- (6- (hydroxyimino) methyl) pyridin-2- Ill) Buta-3-in-1-yl) Tetrahydrofuran-2-carboxamide 57:

Add 1.2 N HCl (185 μL, 0.610 mmol, 10 eq) to a dry MeOH stirred solution (5 mL) of Oxime 56 (30 mg, 0.061 mmol, 1 eq) and stir the reaction mixture at 55 ° C for 5 hours. did. Upon completion, the reaction mixture is concentrated directly under reduced pressure and the residue is purified by reverse phase column chromatography (1: 4 MeOH / H ₂ O) to give salt 57 as a white solid in quantitative yield. rice field. IR (neat method) ν _max 3192, 2927, 1644, 1580, 1448, 1305, 1254, 1045, 989, 808, 726, 642, 533 cm ^-1 ; ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm) ) 8.26 (s, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 7.68 (br d, J = 7.8 Hz, 1H), 7.0 (t, J = 7.8 Hz, 1H), 7.13 (d) , J = 7.5 Hz, 1H), 6.30 (d, J = 7.9 Hz, 1H), 4.85 (s, 1H), 4.54 (s, 1H), 4.39 (br d, J = 4.3 Hz, 1H), 3.63 ( m, 2H), 2.74 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ (ppm) 172.76, 157.47, 154.03, 153.96, 150.15, 149.49, 143.97, 142.67, 138.49, 128.24, 121.22, 120.73 , 90.84, 89.91, 86.78, 82.11, 75.30, 73.56, 38.93, 21.02; HRMS (ESI) ⁺ C ₂₃ H ₂₅ N ₈ O ₅ ⁺ m / z calculated value is 493.1901, measured value is 493.1942.
References 1. Debnath, J. et al. Bioorg. Med. Chem. 2010, 18, 8257-8263

III-Synthesis of bifunctional pseudo-Neca analogs

N-(9-((3aR, 4R, 6R, 6aR) -6-(((3- (6-formylpyridine-2-yl) propa-2-in-1-yl) oxy) methyl) -2, 2-Dimethyltetrahydroflo [3,4-d] [1,3] dioxol-4-yl) -9H-purine-6-yl) benzamide 59:

N-(9-((3aR, 4R, 6R, 6aR) -2,2-dimethyl-6-((propa-2-in-1-yloxy) methyl) -tetrahydroflo [3,4-d] [1 , 3] The synthesis of dioxoll-4-yl) -9H-purine-6-yl) benzamide 58 was accomplished using the known procedure of Silvia, F. et al. ¹ .

Pd [PPh ₃ ] ₄ (77 mg, 0.067 mmol, 0.15 eq) in a degassed THF / Et ₃ N (3 mL / 2 mL) solution of 6-bromopicoline aldehyde 1 (91 mg, 0.490 mmol, 1.1 eq). And CuI (25 mg, 0.134 mmol, 0.3 eq) were added. After degassing the reaction mixture at room temperature for 5 minutes, a degassed THF solution (3 mL) of Alkin 58 (200 mg, 0.445 mmol, 1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography (4: 1 EtOAc / petroleum ether) to the desired bound picoline aldehyde 59 in a concentrated syrup (200 mg, 81%). Got as. IR (neat method) ν _max 2935, 1704, 1609, 1580, 1452, 1248, 1210, 1074, 864, 709, 645, 541 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 9.97 ( s, 1H), 8.76 (s, 1H), 8.32 (s, 1H), 7.94 (d, J = 7.6 Hz, 2H), 7.85-7.77 (m, 2H), 7.63-7.51 (m, 2H), 7.45 (T, J = 7.6 Hz, 2H), 6.25 (d, J = 2.1 Hz, 2H), 5.32 (dd, J = 2.1, 6.2 Hz, 1H), 5.03 (dd, J = 2.1, 6.2 Hz, 1H) , 4.56 (q, J = 2.9 Hz, 1H), 4.37 (s, 2H), 3.89-3.77 (m, 2H), 1.61 (s, 3H), 1.37 (s, 3H); ¹³ C NMR (100 MHz, 100 MHz, CDCl ₃ ) δ (ppm) 192.58, 164.85, 152.75, 152.59, 151.49, 149.28, 142.85, 141.91, 137.53, 13335, 132.81, 131.23, 128.78, 127.81, 123.24, 120.91, 114.32, 91.61, 85.94, 85.47, 85.20, 84.55 , 70.32, 59.09, 27.12, 25.28: HRMS (ESI) ⁺ C ₂₉ H ₂₇ N ₆ O ₆ ⁺ m / z calculated value is 555.2005, measured value is 555.1987.

６－（３－（（（３ａＲ、４Ｒ、６Ｒ、６ａＲ）－６－（６－アミノ－９Ｈ－プリン－９－イル）－２，２－ジメチルテトラヒドロフロ［３，４－ｄ］［１，３］ジオキソール－４－イル）メトキシ）プロパ－１－イン－１－イル）ピコリンアルデヒドオキシム ６１：

N- (9-((3aR, 4R, 6R, 6aR) -6-(((3- (6- (hydroxyimino) methyl) pyridin-2-yl) propa-2-in-1-yl) oxy) Methyl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] dioxol-4-yl) -9H-purine-6-yl) benzamide 60: and

6-(3-(((3aR, 4R, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -2,2-dimethyltetrahydroflo [3,4-d] [1, 3] Dioxol-4-yl) methoxy) propa-1-in-1-yl) picoline aldehyde oxime 61:

A dry ethanol solution of picoline aldehyde 59 (200 mg, 0.361 mmol, 1 eq), hydroxylamine hydrochloride (50 mg, 0.722 mmol, 2 eq), and CH ₃ CO ₂ Na (89 mg, 1.083 mmol, 3 eq) (10). mL) was refluxed and stirred for 16 hours. Upon completion, the reaction mixture is concentrated under reduced pressure, the residue is purified by column chromatography and first eluted from DCM to MeOH / DCM (2:98) to make 60 a white solid (80 mg, 39%). ). IR (neat method) ν _max 3196, 2924, 1698, 1610, 1581, 1453, 1246, 1210, 1075, 907, 727, 644, 551 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.83 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.99-7.89 (m, 2H), 7.54-7.27 (m, 6H), 6.27 (d, J = 2.3 Hz, 2H) , 5.31 (dd, J = 2.3, 6.0 Hz, 1H), 5.03 (dd, J = 2.3, 6.1 Hz, 1H), 4.48 (br q, J = 3.4 Hz, 1H), 4.37, 4.30 (2d, J =) 16.1 Hz, 2H), 3.88 (dd, J = 3.4, 10.3 Hz, 1H), 3.76 (dd, J = 4.0, 10.3 Hz, 1H), 1.62 (s, 3H), 1.38 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 165.11, 152.73, 152.22, 151.35, 149.67, 149.37, 141.87, 136.74, 133.45, 132.69, 128.63, 127.92, 127.22, 122.87, 120.30, 114.28, 91.87, 86.05, 85.03, 84.34, 81.89, 70.23, 59.17, 27.11, 25.26; HRMS (ESI) ⁺ C ₂₉ H ₂₈ N ₇ O ₆ ⁺ m / z calculated value is 570.2075, measured value is 570.2096.

Further elution (5:95 MeOH / DCM) gave 61 as a white solid (75 mg, 45%). IR (neat method) ν _max 3176, 2925, 1639, 1450, 1374, 1207, 1077, 978, 865, 796, 717, 648, 510 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.30 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.64 to 7.52 (m, 2H), 7.26 (s, 1H), 7.01 to 6.87 (m, 2H), 6.20 (d, J = 1.8 Hz, 2H), 5.35 (m, 1H), 5.03 (m, 1H), 4.57 (m, 1H), 4.35 (m, 2H), 3.88-3.76 (m, 2H), 1.61 (s, 3H) ), 1.38 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 155.35, 152.55, 152.47, 149.34, 149.08, 141.96, 139.32, 136.75, 132.82, 127.10, 119.93, 114.13, 91.70, 86.10 , 85.72, 84.86, 84.38, 81.88, 70.21, 59.11, 27.07, 25.27; HRMS (ESI) ⁺ C ₂₂ H ₂₄ N ₇ O ₅ ⁺ m / z calculated value is 466.1812, actual measurement value is 466.1833.
References 1. Silvia, F. et al. J. Med. Chem. 2015, 58, 8269-8284

Synthesis of IV-bifunctional 3-methoxypyridin aldoxim analogs
Synthesis of 3-methoxy-6- (5-phenylpentyl) picoline aldehyde oxime 65:

3-Methoxy-6- (5-phenylpenta-1-in-1-yl) picoline aldehyde 63:

Pd [PPh ₃ ] ₄ (60 mg, 60 mg, in a degassed THF / Et ₃ N (4 mL / 2 mL) solution of commercially available 6-bromo-3-methoxypicoline aldehyde 62 (75 mg, 0.347 mmol, 1.0 eq). 0.052 mmol (0.15 eq) and CuI (20 mg, 0.104 mmol, 0.3 eq) were added. After degassing the reaction mixture at room temperature for 5 minutes, alkyne 3 (50 mg, 0.347 mmol, 1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. Upon completion (monitored by TLC), the reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography (1: 4 EtOAc / PE) to give the desired bound methoxypiconaldehyde 63 a colorless liquid. Obtained as (80 mg, 83%). R _f (30% EtOAc + PE) 0.25; IR (neat method) ν _max 2941, 2230, 1709, 1552, 1466, 1267, 1007, 747, 699, 542 cm ^-1 ; ¹ H NMR (400 MHz, CDCl) ₃ ) δ (ppm) 10.21 (s, 1H, H ₁₈ ), 7.52 (d, J = 8.8 Hz, 1H, H ₄ ), 7.33 (d, J = 8.8 Hz, 1H, H ₅ ), 7.28-7.13 ( m, 5H, H ₁₃ -H ₁₇ ), 3.93 (s, 3H, -OMe), 2.74 (t, J = 7.5 Hz, 2H, H ₁₁ ), 2.39 (t, J = 7.1 Hz, 2H, H ₉ ) , 1.91 (5-fold line, J = 7.1, 7.5 Hz, 2H, H ₁₀ ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 195.52 (C18), 156.25, 141.28, 140.73, 136.02, 132.0, 128.44 , 128.32, 125.91, 120.41 (Ar), 90.27 (C7), 79.44 (C8), 56.03 (-OMe), 34.86 (C11), 29.76 (C10), 18.72 (C9); HRMS (ESI) ⁺ C ₁₈ H ₁₈ The m / z calculated value of N ₁ O ₂ ⁺ is 280.1332, and the measured value is 280.1348.

3-Methoxy-6- (5-phenylpenta-1-in-1-yl) picoline aldehyde oxime 64:

Dry ethanol solution (3 mL) of aldehyde 63 (45 mg, 0.161 mmol, 1 eq), hydroxylamine hydrochloride (22 mg, 0.322 mmol, 2 eq), and CH ₃ CO ₂ Na (40 mg, 0.483 mmol, 3 eq). Was refluxed and stirred for 16 hours. Upon completion (monitored by TLC), the solid is filtered off with a short Celite pad, the solvent is evaporated under reduced pressure and the residue is purified by column chromatography (3: 7 EtOAc / PE) to oxime. 64 was obtained as a white solid (45 mg, 95%). R _f (50% EtOAc + PE) 0.35; IR (neat method) ν _max 3247, 2938, 2234, 1564, 1463, 1263, 975, 828, 745, 698, 649, 487 cm ^-1 ; ^{* 1} H NMR (400 MHz, CDCl ₃ ) δ (ppm) 10.42 (br s, 1H, OH), 8.42, 8.10 (2s, 1.2H, H ₁₈ , H _18' ), 7.46-7.19 (m, 7.6 H, Ar), 3.94, 3.91 (2s, 3.6H, -OMe), 2.81, 2.80 (2t, J = 7.5 Hz, 2.4H, H ₁₁ , H _11' ), 2.47, 2.44 (2t, J = 7.1 Hz, 2.4H, H) ₉ , H _9' ), 2.02-1.92 (m, 2.4H, H ₁₀ , H _10' ); ^{* 13} C NMR (100 MHz, CDCl ₃ ) δ (ppm) 153.54, 151.66, 147.87, 141.41, 141.17, 140.65 , 140.23, 136.37, 135.53, 131.86, 129.18, 128.47, 128.34, 128.29, 127.83, 125.93, 125.84, 119.29, 118.69 (Ar), 90.98, 89.24 (C7), 79.93, 78.76 (C8), 55.93, 55.70 (-OMe) ), 34.85, 34.76 (C11), 29.86, 29.73 (C10), 18.74, 18.57 (C9) (* cis-trans isomers in a 1: 5 ratio); HRMS (ESI) ⁺ C ₁₈ H ₁₈ N ₂ NaO ₂ The ⁺ m / z calculated value is 317.1260, and the measured value is 317.1256.

3-Methoxy-6- (5-phenylpentyl) picoline aldehyde oxime 65:

To a degassed dry EtOAc solution (2 mL) of methoxypyridin aldoxime 64 (25 mg, 0.085 mmol, 1 eq) was added 10% Pd / C (4.5 mg, 0.042 mmol, 0.5 eq). After washing 3 times with H ₂ , the reaction mixture was stirred at room temperature under H ₂ (1 atm) for 3 hours. Upon completion (monitored by TLC), the catalyst is filtered off with a short column of Celite, the solvent is evaporated and the residue is purified by column chromatography (1: 9 EtOAc / PE) to Oxime 65. Was obtained as a colorless liquid (24 mg, 95%). R _f (50% EtOAc + PE) 0.40; IR (neat method) ν _max 3253, 2927, 2855, 1570, 1464, 1269, 1127, 975, 746, 698 cm ^-1 ; ^{* 1} H NMR (400 MHz, 400 MHz, CDCl ₃ ) δ (ppm) 8.40, 8.02 (2s, 1.2H, H ₁₈ , H _18' ), 7.24-6.96 (m, 9.4 H, Ar), 3.79, 3.78 (2s, 3.6H, —— OMe), 2.70 ~ 2.62 (m, 2.5H, H ₁₁ , H _11' ), 2.55 ~ 2.49 (m, 2.5H, H ₇ , H _7' ), 1.68 ~ 1.52 (m, 5 H, H ₈ , H _8' , H ₁₀ , H _10' ), 1.35 to 1.28 (m, 2.5H, H ₉ , H _9' ); ^{* 13} C NMR (100 MHz, CDCl ₃ ) δ (ppm) 154.25, 152.57, 150.87, 150.67, 146.82, 142.71 , 142.47, 140.12, 139.24, 137.09, 128.35, 128.21, 128.16, 125.59, 125.51, 125.06, 123.58, 119.91, 119.18 (Ar), 55.82, 55.63 (-OMe), 37.23, 36.25 (C11), 35.78, 35.73 (C7) ), 31.25, 31.12 (C10), 29.85, 29.67 (C9), 28.90, 28.65 (C8) (* cis-trans isomer is 1: 4 ratio); HRMS (ESI) ⁺ C ₁₈ H ₂₃ N ₂ O ₂ The ⁺ m / z calculated value is 299.1754, and the measured value is 299.1740.

Synthesis of methoxypyridin aldoxim analogs from V-quinoline:

3-Methoxy-6- (4- (quinoline-4-ylamino) buta-1-in-1-yl) picoline aldehyde 66:

Pd [PPh ₃ ] ₄ (71 mg,) in a commercially available 6-bromo-3-methoxypicoline aldehyde 62 (97 mg, 0.448 mmol, 1.1 eq) degassed THF / Et ₃ N (3 mL / 3 mL) solution. 0.061 mmol (0.15 eq) and CuI (23 mg, 0.122 mmol, 0.3 eq) were added. After degassing the reaction mixture at room temperature for 5 minutes, a THF solution (3 mL) of Alkin 24 (80 mg, 0.408 mmol, 1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. Upon completion (monitored by TLC), the reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography (1: 9 MeOH / EtOAc) to give the desired bound methoxypiconaldehyde 66 pale yellow. Obtained as a solid (126 mg, 93%). R _f (30% MeOH + EtOAc) 0.25; IR (Neat Method) ν _max 3281, 2926, 2233, 1704, 1582, 1434, 1267, 1126, 1009, 763, 694, 521, 494 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 10.21 (s, 1H, H ₁₈ ), 7.52 (d, J = 8.8 Hz, 1H, H ₄ ), 7.33 (d, J = 8.8 Hz, 1H, H ₅ ) ), 7.28-7.13 (m, 5H, H ₁₃ -H ₁₇ ), 3.93 (s, 3H, -OMe), 2.74 (t, J = 7.5 Hz, 2H, H ₁₁ ), 2.39 (t, J = 7.1 Hz) , 2H, H ₉ ), 1.91 (5-fold line, J = 7.1, 7.5 Hz, 2H, H ₁₀ ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 195.52 (C18), 156.25, 141.28, 140.73 , 136.02, 132.0, 128.44, 128.32, 125.91, 120.41 (Ar), 90.27 (C7), 79.44 (C8), 56.03 (-OMe), 34.86 (C11), 29.76 (C10), 18.72 (C9); HRMS (ESI) ) ⁺ C ₁₈ H ₁₈ N ₁ O ₂ ⁺ m / z calculated value is 280.1332, measured value is 280.1348.

3-Methoxy-6- (4- (quinoline-4-ylamino) buta-1-in-1-yl) picoline aldehyde oxime 67:

A dry ethanol solution (5 mL) of aldehyde 66 (100 mg, 0.362 mmol, 1 eq), hydroxylamine hydrochloride (50 mg, 0.724 mmol, 2 eq), and CH ₃ CO ₂ Na (89 mg, 1.086 mmol, 3 eq). ) Was refluxed and stirred for 16 hours. Upon completion (monitored by TLC), the solid is filtered off with a short Celite pad, the solvent is evaporated under reduced pressure and the residue is purified by column chromatography (1: 9 MeOH / EtOAc). Oxime 67 was obtained as a white solid (65 mg, 62%). R _f (30% MeOH + EtOAc) 0.2; IR (neat method) ν _max 3319, 2924, 1897, 1586, 1460, 1242, 1115, 982, 829, 760, 649, 524 cm ^-1 ; ¹ H NMR ( 500 MHz, DMSO-d ₆ ) δ (ppm) 11.63 (br s, 1H, OH), 8.41 (d, J = 5.2 Hz, 1H, Ar), 8.22 (s, 1H, -C-NOH), 8.21 ( d, J = 8.5 Hz, 1H, Ar), 7.79 (d, J = 8.5 Hz, 1H, Ar), 7.61 (t, J = 7.6 Hz, 1H, Ar), 7.50-7.36 (m, 4 H, Ar) ), 6.58 (d, J = 5.4 Hz, 1H, Ar), 3.85 (s, 3H, -OMe), 3.58 (q, J = 5.9, 7.1 Hz, 2H, H ₁₀ ), 2.83 (t, J = 7.1) Hz, 2H, H ₉ ); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ (ppm) 153.77, 151.22, 149.97, 148.83, 145.06, 140.87, 134.59, 129.57, 129.24, 128.54, 124.42, 122.07, 120.24, 119.30, 98.94 (Ar), 87.06 (C8), 81.50 (C7), 56.46 (-OMe), 41.75 (C10), 19.08 (C9); HRMS (ESI) ⁺ C ₂₀ H ₁₉ N ₄ O ₂ ⁺ m / z The calculated value is 347.1503, and the measured value is 347.1491.

4-((4- (6-((Hydroxyimino) methyl) -5-methoxypyridin-2-yl) buta-3-in-1-yl) amino) quinoline-1-ium chloride 68:

To a solution of compound 67 (9.5 mg) in MeOH / H ₂ O (0.5 mL / 0.5 mL) was added 1.2 N HCl (0.1 mL), stirred for 2 minutes and left at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give HCl salt 68 as a white solid in quantitative yield. IR (neat method) ν _max 3186, 3099, 2838, 2237, 1615, 1593, 1449, 1277, 1007, 760, 649, 530, 491 cm ^-1 ; ¹ H NMR (500 MHz, D ₂ O) δ (ppm) ) * 8.18 to 8.08 (m, 3H, Ar), * 7.96 to 7.91 (m, 1.5 H, Ar), * 7.74 to 7.70 (m, 1.5 H, Ar), * 7.62 to 7.54 (m, 3H, Ar) , * 7.51-7.40 (m, 4.5 H, Ar), * 6.73-6.70 (m, 1.5 H, Ar), * 3.92 (s, 1.5H, -OMe), * 3.84 (the, J = 6.6 Hz, 1H) , H _10' ), 3.80 (s, 3H, -OMe), 3.75 (t, J = 6.6 Hz, 2H, H ₁₀ ), * 2.98 (t, J = 6.6 Hz, 1H, H _9' ), 2.89 ( t, J = 6.6 Hz, 2H, H ₉ ); ^{* 13} C NMR (125 MHz, D ₂ O) δ (ppm) 156.49, 154.95, 142.15, 142.03, 141.86, 141.45, 140.04, 139.68, 138.68, 137.60, 137.00 , 134.19, 131.06, 130.37, 128.51, 128.26, 17.55, 127.52, 125.38, 122.39, 120.29, 120.22, 119.12, 116.93, 116.81, 98.55, 98.47 (Ar), 94.74 (C8), 76.76 (C7), 57.71, 57.22 ( -OMe), 41.65, 41.10 (C10), 19.5 (C9) (* cis-trans isomer is 1: 2 ratio); HRMS (ESI) ⁺ C ₂₀ H ₂₀ ClN ₄ O ₂ ⁺ m / z calculated value Is 347.1503, and the measured value is 347.1461.

3-Methoxy-6- (4- (quinoline-4-ylamino) butyl) picoline aldehyde oxime 69:

To a degassed dry EtOAc solution (2 mL) of methoxypyridin aldoxime 67 (25 mg, 0.085 mmol, 1 eq) was added 10% Pd / C (4.5 mg, 0.042 mmol, 0.5 eq). After washing 3 times with H ₂ , the reaction mixture was stirred at room temperature under H ₂ (1 atm) for 3 hours. Upon completion (monitored by TLC), the catalyst is filtered off with a short column of Celite, the solvent is evaporated under reduced pressure and the residue is purified by column chromatography (1: 9 EtOAc / PE). , Oxime 69 was obtained as a colorless liquid (24 mg, 95%). R _f (50% EtOAc + PE) 0.40; IR (neat method) ν _max 3327, 2923, 2583, 1582, 1457, 1272, 1126, 968, 763, 694, 540, 473 cm ^-1 ; ^{* 1} H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.42 (2s, 1H, H ₁₈ , H _18' ), 8.32 (d, J = 5.7 Hz, 1H, Ar), 8.10 (dd, J = 1.2, 8.6 Hz, 1H, Ar), 7.79 (d, J = 1.2, 8.6 Hz, 1H, Ar), 7.64 (m, 1 H, Ar), 7.44 (m, 1H, Ar), 7.39 (d, J = 8.7 Hz, 1H) , Ar), 7.26 (d, J = 8.7 Hz, 1H, Ar), 6.50 (d, J = 5.8 Hz, 1H, Ar), 3.87 (s, 3H, -OMe), 3.42 (t, J = 6.9 Hz) , 1H, H ₁₀ ), 3.42 (t, J = 6.9 Hz, 1H, H ₁₀ ), 2.83 (t, J = 7.5 Hz, 1H _, H ₇ ), 1.87 to 1.77 (m, 4H, H _8, H ₉ ) ); ^{* 13} C NMR (100 MHz, CDCl ₃ ) δ (ppm) 155.21, 154.35, 153.13, 150.73, 148.33, 145.93, 140.73, 138.63, 130.85, 128.33, 125.82, 122.51, 121.43, 120.31, 99.30 (Ar), 56.53 (-OMe), 43.86 (C10), 37.37 (C7), 28.95 (C9), 28.82 (C8) (* cis-trans isomer ratio 1: 4); HRMS (ESI) ⁺ C ₂₀ H ₂₃ N The m / z calculated value of ₄ O ₂ ⁺ is 351.1816, and the measured value is 351.1827.

4-((4- (6-((Hydroxyimino) methyl) -5-methoxypyridin-2-yl) butyl) amino) quinoline-1-ium 70:

To a solution of compound 69 (8 mg) in MeOH / H ₂ O (0.5 mL / 0.5 mL) was added 1.2 N HCl (0.1 mL), stirred for 2 minutes and left at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the HCl salt 70 as a white solid in quantitative yield. IR (neat method) ν _max 3237, 3111, 2926, 1617, 1594, 1452, 1291, 1011, 764, 663, 592 cm ^-1 ; ¹ H NMR (500 MHz, D ₂ O) δ (ppm) 8.20 (s) , 1H, H ₁₈ ), 8.19 (d, J = 8.6 Hz, 1H _, Ar), 8.04 (d, J = 8.6 Hz, 1H _, Ar), 7.94-7.87 (m, 2H _, Ar), 7.75 (dd, dd, J = 8.6, 18.8 Hz, 1H _, Ar), 7.64 (t, J = 8.8 Hz, 1H _, Ar), 6.64 (d, J = 7.2 Hz, 1H _, Ar), 3.93 (s, 3H, -OMe), 3.55 (t, J = 6.5 Hz, 1H _, H ₁₀ ), 3.01 (t, J = 6.8 Hz, 1H _, H ₇ ), 1.95 to 1.80 (m, 4H, H _8, H ₉ ); ^{* 13} C NMR ( 125 MHz, D ₂ O) δ (ppm) 156.07, 154.21, 150.14, 141.63, 139.57, 137.60, 134.14, 133.86, 129.10, 128.69, 127.47, 122.29, 120.27, 116.86, 98.31 (Ar), 57.45 (-OMe), 42.83 (C10), 32.20 (C7), 26.12 (C9), 25.81 (C8) (* cis-trans isomer is 1: 2 ratio); HRMS (ESI) ⁺ C ₂₀ H ₂₃ N ₄ O ₂ ⁺ m The calculated value of / z is 351.1816, and the measured value is 351.1782.

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -N- (4- (6-(-(hydroxyimino) methyl) -5-methoxypyridin-2- Ill) Buta-3-in-1-yl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] dioxol-4-carboxamide 72:

Pd [PPh ₃ ] ₄ (140 mg,) in a degassed THF / Et ₃ N (5 mL / 5 mL) solution of commercially available 6-bromo-3-methoxypicoline aldehyde 62 (192 mg, 0.887 mmol, 1.1 eq). 0.121 mmol (0.15 eq) and CuI (46 mg, 0.242 mmol, 0.3 eq) were added. The reaction mixture was degassed at room temperature for 5 minutes, then a solution of Alkin 54 (300 mg, 0.806 mmol, 1 eq) in THF (5 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. Upon completion (monitored by TLC), the reaction mixture is concentrated under reduced pressure and the residue is passed through a small filter column (5:95 MeOH / EtOAc) for the desired bound methoxypiconaldehyde 71 (360 mg, 88). %) Was obtained as a pale yellow solid. This crude aldehyde was used directly in the next step without purification.

Dry ethanol (7 mL) of aldehyde 71 (220 mg, 0.433 mmol, 1 eq), hydroxylamine hydrochloride (60 mg, 0.867 mmol, 2 eq), and CH ₃ CO ₂ Na (107 mg, 1.299 mmol, 3 eq). The solution was refluxed and stirred for 16 hours. Upon completion (monitored by TLC), the solid is filtered off with a short Celite pad, the solvent is evaporated and the residue is purified by column chromatography (1: 9 MeOH / EtOAc) to remove oxime 72. Obtained as a white solid (180 mg, 78%). R _f (30% MeOH + EtOAc) 0.2; IR (neat method) ν _max 3185, 2926, 1640, 1464, 1264, 1209, 1090, 971, 868, 797, 647, 510 cm ^-1 ; ¹ H NMR ( 400 MHz, MeOD) δ (ppm) 8.39-8.11 (3s, 3H, Ar, -C = NOH), 7.37 (d, J = 8.6, 1H, H ₄ ), 7.26 (d, J = 8.6 Hz, 1H, H ₅ ), 6.34 (br s, H, -CH), 5.57 (dd, J = 1.8, 6.0 Hz, 1H, -CH), 5.41 (br d, J = 6.0 Hz, 1H, -CH), 4.68 ( d, J = 1.8 Hz, 1H, -CH), 3.89 (s, 3H, -OCH ₃ ), 3.21 (m, 1H, -CH ₂ ), 3.09 (m, 1H, -CH ₂ ), 2.27 (m, 1H, -CH ₂ ), 2.10 (m, 1H, -CH ₂ ), 1.57 (s, 3H, -CH ₃ ), 1.37 (s, 3H, -CH ₃ ); ¹³ C NMR (100 MHz, MeOD) δ (Ppm) 172.07, 157.33, 155.15, 153.99, 150.30, 145.21, 142.55, 141.69, 135.92, 129.89, 120.84, 120.49, 115.17 (Ar), 92.41 (C16), 88.65 (C15), 87.34 (C8), 85.36 (C14) ), 85.26 (C13), 81.58 (C7), 56.74 (C30), 38.79 (C10), 27.29 (C28), 25.54 (C29), 20.47 (C9); HRMS (ESI) ⁺ C ₂₄ H ₂₇ N ₈ O ₆ The m / z calculated value of ⁺ is 523.2048, and the measured value is 523.2038.

Synthesis of VI-trifunctional Neca compounds

6- (Azidomethyl) picoline aldehyde 75:

The synthesis of methyl 64- (azidomethyl) picolinate 74 was achieved using the well-established procedure of Harekrushna, B et al. ¹ .

DIBAL-H (1 M solution in CH ₂ Cl ₂ , 1.563 mL, 1.563 mmol) in a dry CH ₂ Cl ₂ solution (5 mL) of azide ester 74 (100 mg, 0.521 mmol, 1 eq) at -78 ° C. 3 eq) was added dropwise and the reaction mixture was stirred at −78 ° C. for 5 hours. After completion of the reaction, the reaction mixture was stopped with MeOH (3 mL) and the cooling bath was removed. The mixture was warmed to room temperature, the reaction mixture was diluted with H ₂ O and extracted with EtOAc. The mixed organic layer was dried with DDL ₄ . The solid was filtered off and the solvent was evaporated to give aldehyde 75. This crude aldehyde 75 was provided directly to the next step without purification. IR (neat method) ν _max 2836, 2098, 1709, 1591, 1457, 1255, 990, 777, 641 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 10.04 (s, 1H), 7.94 ~ 7.86 (m, 2H), 7.56 (m, 2H), 4.57 (s, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm) 193.07, 156.73, 152.59, 138.11, 126.05, 102.78, 55.15; HRMS (ESI) ⁺ C ₇ H ₇ N ₄ O ₁ ⁺ m / z calculated value 163.0604, measured value 163.0614.

6- (Azidomethyl) Picoline Aldehyde Oxime 76:

A dry ethanol solution (5 mL) of crude picoline aldehyde 75 (0.521 mmol, 1 eq), hydroxylamine hydrochloride (73 mg, 1.042, 2 eq), and CH ₃ CO ₂ Na (128 mg, 1.563 mmol, 3 eq). , Stirred at 80 ° C for 16 hours. Upon completion, filter through a short column of Celite to remove the solid, evaporate the solvent, purify the residue by column chromatography (1: 9 EtOAc / PE) and oxime 76 in a concentrated syrup (70 mg). , 76%). IR (neat method) ν _max 3182, 3010, 2889, 2084, 1572, 1590, 1459, 12666, 1233, 1158, 994, 966, 782, 741, 651, 619, 501 cm ^-1 ; ¹ H NMR (400 MHz) , CD ₃ OD) δ (ppm) 8.10 (s, 1H), 7.86-7.76 (m, 2H), 7.40 (dd, J = 1.8, 6.8 Hz, 2H), 4.48 (s, 2H); ¹³ C NMR ( 100 MHz, CD ₃ OD) δ (ppm) 157.29, 153.94, 149.93, 139.26, 1323.66, 120.86, 56.16; HRMS (ESI) ⁺ C ₇ H ₈ N ₅ O ₁ ⁺ m / z calculated value is 178.0721, measured value Is 178.0723508.1867.

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -N- (2- (1-((6-(-(hydroxyimino) methyl) pyridine-2- Ile) Methyl) -1H-1,2,3-triazole-4-yl) Ethyl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] Dioxol-4-carboxamide 77:

CuSO ₄ (17 mg, 0.107 mmol, 0.4 eq), sodium ascorbate (21 mg) in a t-BuOH / H ₂ O (2 mL / 1.5 mL) stirring solution of oxime 76 (52 mg, 0.295 mmol, 1.1 eq). , 0.107 mmol, 0.4 eq), and alkyne 54 (100 mg, 0.268 mmol, 1 eq). The reaction mixture was stirred at 80 ° C. for 6 hours. Upon completion (monitored by TLC), the reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography (5:95 MeOH / EtOAc) to give the desired triazole compound 77 a white solid (85). Obtained as mg, 58%). IR (neat method) ν _max 3192, 2924, 1644, 1598, 1458, 1376, 1209, 1155, 1057, 992, 868, 797, 648, 511 cm ^-1 ; ¹ H NMR (400 MHz, CD ₃ OD) δ (Ppm) 8.20 (s, 1H), 8.08 (s, 1H), 8.05 (s, 1H), 7.75-7.70 (m, 2H), 7.12 (m, 1H), 6.30 ((d, J = 1.7 Hz,) 1H), 5.62 (s, 2H), 5.50 (dd, J = 1.9, 6.1 Hz, 1H), 4.62 (d, J = 1.9 Hz, 1H), 3.24 to 3.01 (m, 2H), 2.61 to 2.41 (m) , 2H), 1.57 (s, 3H), 1.38 (s, 3H); ¹³ C NMR (100 MHz, CD ₃ OD) δ (ppm) 171.91, 157.38, 156.08, 153.97, 150.27, 150.06, 146.45, 142.54, 139.28 , 124.46, 123.53, 121.07, 120.55, 115.24, 92.65, 88.38, 85.28, 85.06, 56.09, 39.64, 27.31, 25.91, 25.55; HRMS (ESI) ⁺ C ₂₄ H ₂₈ N ₁₁ O ₅ ⁺ m / z calculated value 550.2237, the measured value is 550.2269.

(2S, 3S, 4R, 5R) -5- (6-amino-9H-purine-9-yl) -3,4-dihydroxy-N- (2- (1-((6- (-(hydroxyimino))) -Methyl) Pyridine-2-yl) Methyl) -1H-1,2,3-triazole-4-yl) Ethyl) Tetrahydrofuran-2-carboxamide hydrochloride 78:

To a dry MeOH stirring solution (2 mL) of triazole 77 (23 mg, 0.042 mmol, 1 eq), add 1.2 N HCl (127 μL, 0.42 mmol, 10 eq) and stir the reaction mixture at 55 ° C for 4 hours. did. Upon completion, the reaction mixture is concentrated directly under reduced pressure and the residue is purified by reverse phase column chromatography (3: 7 MeOH / H ₂ O) to whiten HCl salt 78 (15 mg, 72%). Obtained as a solid. IR (neat method) ν _max 3196, 1640, 1588, 1458, 1427, 1306, 1254, 1113, 1054, 997, 796, 647 cm ^-1 ; ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm) 7.99 (S, 1H), 8.89 (s, 1H), 7.83 (s, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.29 (t, J = 9.3 Hz, 1H), 7.20 (s, 1H) , 7.13 (t, J = 7.8 Hz, 1H), 5.77 (d, J = 8.3 Hz, 1H), 5.44-5.38 ((2d, J = 14.8 Hz, 2H), 4.43 (s, 1H), 4.32 (br d, J = 5.0 Hz, 1H), 4.08 (dd, J = 4.8, 8.3 Hz, 1H), 3.61 (m, 1H), 3.35 (m, 1H), 3.08-299 (m, 1H), 3.96-288 (M, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ (ppm) 172.32, 155.44, 153.78, 151.99, 150.84, 147.61, 142.13, 138.97, 124.62, 124.41, 121.56, 119.75, 89.21, 85.20, 73.72 , 72.06, 55.28, 49.50 (MeOH), 39.92, 24.77; HRMS (ESI) ⁺ C ₂₁ H ₃₃₄ N ₁₁ O ₅ ⁺ m / z calculated value is 510.1957, measured value is 510.1956.
References 1. Harekrushna, B. et al. Chem. Eur. J. 2015, 21, 10179-10184

VII-Synthesis of trifunctional pseudo-Neca compounds

N-(9-((3aR, 4R, 6R, 6aR) -6-(((1-((6-(-(hydroxyimino) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-Triazole-4-yl) methoxy) methyl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] dioxol-4-yl) -9H-purine-6-yl) benzamide 79:

CuSO ₄ (17 mg, 0.045 mmol, 0.2 eq), sodium ascorbate (18 mg) in a t-BuOH / H ₂ O (2 mL / 1.5 mL) stirring solution of oxime 76 (44 mg, 0.245 mmol, 1.1 eq). , 0.045 mmol, 0.2 eq), and alkyne 58 (100 mg, 0.223 mmol, 1 eq). The reaction mixture was stirred at 80 ° C. for 6 hours. Upon completion (monitored by TLC), the reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography (pure EtOAc-5: 95 MeOH / EtOAc) to whiten the desired triazole compound 79. Obtained as a solid (100 mg, 72%). IR (neat method) ν _max 2924, 1698, 1610, 1581, 1455, 1248, 1211, 1070, 994, 796, 709, 645, 563 cm ^-1 ; ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm) ) 10.88 (br s, 1H), 9.31 (br s, 1H), 8.77 (s, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 7.95-7.80 (m, 3H), 7.51-7.28 (M, 5H), 6.99 (d, J = 7.5 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 5.63 (s, 2H), 5.21 (dd, J = 2.2, 5.9 Hz, 1H) , 4.98 (dd, J = 1.6, 5.9 Hz, 1H), 4.65-4.50 (m, 3H), 3.82 (dd, J = 2.2, 10.6 Hz, 1H), 3.70 (dd, J = 3.0, 10.6 Hz, 1H) ), 1.61 (s, 3H), 1.37 (s, 3H); ¹³ C NMR (100 MHz, CD ₃ OD) δ (ppm) 165.35, 154.38, 152.69, 151.64, 151.44, 150.02, 149.19, 143.91, 141.90, 137.62 , 133.31, 128.56, 127.93, 124.13, 122.78, 122.07, 120.42, 114.09, 92.26, 86.27, 85.28, 81.85, 70.67, 64.47, 55.03, 27.11, 25.24; HRMS (ESI) ⁺ C ₃₀ H ₃₁ N ₁₀ O ₆ ⁺ The m / z calculated value is 627.2414, and the measured value is 627.2423.

Example 2: In vitro reactivation of human acetylcholinesterase (hAChE) by the compound of the present invention O-ethyl = S- [2- (diisopropylamino) ethyl] = methylphosphonothioate (VX), tabun, sarin , Or the activation properties of compounds 57, 78, 25, and 26 of Example 1 in hAChE inhibited by paraoxon were tested.

2-PAM (Pralidoxime, or 2-[(E)-(Hydroxyimino) Methyl] -1-Methylpyridinium) and HI6 (Assoxime Chloride, or [1-[(4-Carbamoylpyridin-1-ium-1-yl)) ) Methyl-methyl] pyridine-2-iriden] methyl-oxoazanium dichloride) was used as a comparative compound.

As a procedure, materials and methods have already been described in International Application WO2017021319, European Journal of Medicinal Chemistry 2014, 78, 455-467, and J. Med. Chem. 2018, 61, 7630-7639.

Measurement of IC ₅₀ Recombinant hAChE was produced and purified as previously described (see Carletti et al 2008 J Am Chem Soc 130 (47): 1601 1-20). The compound was dissolved in MeOH to make a 5 mM or 10 mM storage solution and further diluted with phosphate buffer (sodium phosphate; 0.1 M, pH 7.4). The activity of recombinant hAChE is spectroscopic in the presence of various concentrations of oxime in 1 mL Ellman buffer (sodium phosphate; 0.1 M, pH 7.4, 0.1% BSA, 0.5 mM DTNB, 25 ° C). It was measured by the photometric method (absorbance at 412 nm). Measurements were performed at least twice for each concentration tested. The concentration of the compound producing 50% of the enzyme inhibition was determined by a nonlinear approximation using ProFit (Quantumsoft) with a standard IC ₅₀ formula:% activity = 100 * IC ₅₀ / (IC ₅₀ + [Ox]).

Inhibition of hAChE by OPNA Recombinant hAChE was generated and purified as previously described (see http://www.ncbi.nlm.nih.gov/pubmed/18975951). VX and tabun were provided by DGA maitrise NRBC (Vert le Petit, France). The conservative solution of VX, sarin, tabun, and paraoxon was a 5 mM isopropanol solution. Inhibition of 120 μM hAChE was performed with 5-fold excess OPNA and in 25 ° C Tris buffer (20 mM, pH 7.4, 0.1% BSA). After 20 minutes of culture, the inhibited hAChE was desalted on a PD-10 column (GE Healthcare).

OPNA-inhibited hAChE reactivation
OPNA-inhibited hAChE was cultured at 37 ° C with at least 4- or 5-fold concentrations of oxime in phosphate buffer (0.1 M, pH 7.4, 0.1% BSA). The final concentration of MeOH in the culture mixture was less than 2% and did not affect the stability of the enzyme. At time intervals ranging from 1 to 10 minutes, depending on the rate of reactivation, 10 divided amounts of each solution containing various concentrations of oxime, 1 mL Ellman buffer (0.1) for measuring hAChE activity. Transferred to a cuvette containing 1 mM acetylthiocholine in M phosphate, pH 7.4, 0.1% BSA, 0.5 mM DTNB, 25 ° C).

E－P：酵素
Ox：オキシム化合物
E－Pox：酵素－オキシム複合体 Enzyme activity in the control remained constant during the experiment. The percentage of reactivated enzyme (% E _react ) was calculated as the ratio of the recovered enzyme activity to the activity in the control. The apparent reactivation rate constant for each oxime concentration, the dissociation constant Κ _D for the inhibited enzyme-oxime complex (E-POx), and the maximum reactivation rate constant kr are derived from the following equations for the standard oxime. It was calculated by a non-linear approximation in ProFit (Quantumsoft) using a concentration-dependent reactivation equation.

EP: Enzyme
Ox: Oxime compound
E-Pox: Enzyme-Oxime Complex

The results are as follows (Tables 1 and 2).

Table 1 shows that compound 57 shows a higher reactivation rate (kr / min) for VX, tabun, sarin, and paraoxone compared to control 2-PAM and HI6, and compound 78 , Represents a higher reactivation rate (kr / min) for VX, tabun, and sarin compared to 2-PAM and HI6 in the reference.

Compounds 25 and 26 show a strong affinity for AChE inhibited by VX or sarin. These compounds show higher reactivation (kr2 / mM · min) than 2-PAM and HI6.

Table 2 shows that compounds 25 and 26 have very high affinities for AChE, which are higher than those for 2-PAM and HI6. Compound 25 exhibits the highest affinity.

Claims (15)

Equation (I):

[During the ceremony,
R1 is H, or a linear or cyclic (preferably aromatic) C1 _- C ₇ alkoxy group, preferably R1 is H, methoxy or benzyloxy.
-XY- is -CH _2- (CH ₂ ) _n- , -C≡C-,

Or -XY- is Br and R2 does not exist.
n is an integer from 0 to 5 and
R2 is a group selected from alkyl, aryl, aralkyl, heteroaryl, -R3-N (R4) (R5), A group, B group, C group, and D group.

Here, the A group, the B group, the C group, or the D group may be bonded to —X— by an alkyl group, preferably an ethyl group.
R3 is _a C1- _C4 alkyl group, and R4 and R5 are the same or different, and independently H, naphthyl group, 5-fluoroquinoline-4-yl group, quinoline-4-yl group, or 8-yl group. Represents a methoxyquinoline-4-yl group, or R4 and R5, together with a nitrogen atom, are a 4-benzyl-piperazine-1-yl group, or 3,7-dimethyl-2,6-dioxo-2,3,6,7. -Forms a tetrahydro-1H-purine-1-yl group]
One of the compounds of or a pharmaceutically acceptable salt thereof. The following skeleton 1:

[In the formula, R1 is as specified in claim 1]
The compound according to claim 1. The following skeleton 2:

[In the formula, R1 and R2 are as specified in claim 1.]
The compound according to claim 1. R2 is selected from A group, B group, C group, and D group.

The compound according to claim 3, wherein the C or D group is preferably linked to —X— by an alkyl group, more preferably an ethyl group. R2 is alkyl, heteroaryl, aralkyl, or -R3-N (R4) (R5), where
R3 is a C ₁ -C ₄ alkyl group, preferably R3 is selected from methyl, ethyl, and n-propyl.
3. The third aspect of claim 3, wherein R4 is H and R5 is selected from a naphthyl group, a 5-fluoroquinoline-4-yl group, a quinoline-4-yl group, or an 8-methoxyquinoline-4-yl group. Compound. R2 is -R3-N (R4) (R5), where R3 is _a C1- _C4 alkyl group, preferably R3 is selected from methyl, ethyl, and n-propyl, and R4 and R5. Formes a 4-benzyl-piperazin-1-yl group or a 3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-1-yl group with a nitrogen atom. , The compound according to claim 3. The following skeleton 3:

[In the formula, R1 and R2 are as specified in claim 1, and n is an integer of 0 to 5].
The compound according to claim 1. R2 is alkyl, aryl, aralkyl, or -R3-N (R4) (R5), where
R3 is a C ₁ -C ₄ alkyl group, preferably R3 is selected from methyl, ethyl, and n-propyl.
22. Compound. R2 is -R3-N (R4) (R5), where R3 is _a C1- _C4 alkyl group, preferably R3 is selected from methyl, ethyl, and n-propyl, and R4 and R5. 7 is the compound according to claim 7, wherein the compound forms a 4-benzyl-piperazin-1-yl group together with a nitrogen atom. The following skeleton 4:

[In the formula, R1 and R2 are as specified in claim 1.]
The compound according to claim 1. R2 is selected from A, C, and D groups.

The compound according to claim 10, wherein the C or D group is preferably linked to —X— by an alkyl group, more preferably an ethyl group. The following compounds:
6-bromopicoline aldehyde oxime 2:

6- (5-Phenylpenta-1-in-1-yl) picoline aldehyde oxime 5:

6- (5-Phenylpentyl) picoline aldehyde oxime 7:

6- (Pentadeca-1-in-1-yl) Picoline aldehyde oxime 9:

6-Pentadecylpicoline aldehyde oxime 10:

6- (Pyridine-3-ylethynyl) Picoline Aldehyde Oxime 12:

2-((Hydroxyimino) Methyl) -6- (Pyridine-1-ium-3-ylethynyl) Pyridine-1-ium chloride 13:

N- (4- {6-[(hydroxyimino) methyl] pyridin-2-yl} buta-3-in-1-yl) naphthalene-1-amine 19:

N- (4- {6-[(hydroxyimino) methyl] pyridin-2-yl} buta-3-in-1-yl) naphthalene-1-amine 20:

6- (4- (quinoline-4-ylamino) pig-1-in-1-yl) picoline aldehyde oxime 25:

Methyl 3-hydroxy-6- (4- (quinoline-4-ylamino) butyl) picolinate 26:

6-(4-((5-Fluoroquinoline-4-yl) amino) buta-1-in-1-yl) picoline aldehyde oxime 30:

6-(4-((5-Fluoroquinoline-4-yl) amino) butyl) picoline aldehyde oxime 31:

6- (4-((8-Methoxyquinoline-4-yl) amino) buta-1-in-1-yl) picoline aldehyde oxime 36:

6-(4-((8-Methoxyquinoline-4-yl) amino) butyl) picoline aldehyde oxime 37:

6- (3- (4-Benzylpiperazine-1-yl) propa-1-in-1-yl) picoline aldehyde oxime 42:

6- (3- (4-Benzylpiperazine-1-yl) propyl) picoline aldehyde oxime 43:

6- (4- (4-Benzylpiperazine-1-yl) buta-1-in-1-yl) picoline aldehyde oxime 47:

6- (4- (4-Benzylpiperazine-1-yl) butyl) picoline aldehyde oxime 48:

6- (4- (3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-1-yl) pig-1-in-1-yl) picoline aldehyde oxime 51 :

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -N- (4- (6- (hydroxyimino) methyl) pyridin-2-yl) pig-3- In-1-yl) -2,2-Dimethyltetrahydroflo [3,4-d] [1,3] Dioxol-4-carboxamide 56:

(2S, 3S, 4R, 5R) -5- (6-amino-9H-purine-9-yl) -3,4-dihydroxy-N- (4- (6- (hydroxyimino) methyl) pyridin-2- Ill) Buta-3-in-1-yl) Tetrahydrofuran-2-carboxamide 57:

N- (9-((3aR, 4R, 6R, 6aR) -6-(((3- (6- (hydroxyimino) methyl) pyridin-2-yl) propa-2-in-1-yl) oxy) Methyl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] dioxol-4-yl) -9H-purine-6-yl) benzamide 60:

6-(3-(((3aR, 4R, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -2,2-dimethyltetrahydroflo [3,4-d] [1, 3] Dioxol-4-yl) methoxy) propa-1-in-1-yl) picoline aldehyde oxime 61:

3-Methoxy-6- (5-phenylpenta-1-in-1-yl) picoline aldehyde oxime 64:

3-Methoxy-6- (5-phenylpentyl) picoline aldehyde oxime 65:

3-Methoxy-6- (4- (quinoline-4-ylamino) buta-1-in-1-yl) picoline aldehyde oxime 67:

4-((4- (6-((Hydroxyimino) methyl) -5-methoxypyridin-2-yl) buta-3-in-1-yl) amino) quinoline-1-ium chloride 68:

3-Methoxy-6- (4- (quinoline-4-ylamino) butyl) picoline aldehyde oxime 69:

4-((4- (6-((Hydroxyimino) methyl) -5-methoxypyridin-2-yl) butyl) amino) quinoline-1-ium 70:

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -N- (4- (6-(-(hydroxyimino) methyl) -5-methoxypyridin-2- Ill) Buta-3-in-1-yl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] dioxol-4-carboxamide 72:

(3aS, 4S, 6R, 6aR) -6- (6-amino-9H-purine-9-yl) -N- (2- (1-((6-(-(hydroxyimino) methyl) pyridine-2- Ile) Methyl) -1H-1,2,3-triazole-4-yl) Ethyl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] Dioxol-4-carboxamide 77:

(2S, 3S, 4R, 5R) -5- (6-amino-9H-purine-9-yl) -3,4-dihydroxy-N- (2- (1-((6- (-(hydroxyimino))) -Methyl) Pyridine-2-yl) Methyl) -1H-1,2,3-triazole-4-yl) Ethyl) Tetrahydrofuran-2-carboxamide hydrochloride 78:

N-(9-((3aR, 4R, 6R, 6aR) -6-(((1-((6-(-(hydroxyimino) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-Triazole-4-yl) methoxy) methyl) -2,2-dimethyltetrahydroflo [3,4-d] [1,3] dioxol-4-yl) -9H-purine-6-yl) benzamide 79:

Selected from
More preferably, the following compounds:
(2S, 3S, 4R, 5R) -5- (6-amino-9H-purine-9-yl) -3,4-dihydroxy-N- (4- (6- (hydroxyimino) methyl) pyridin-2- Ill) Buta-3-in-1-yl) Tetrahydrofuran-2-carboxamide 57:

6- (4- (quinoline-4-ylamino) pig-1-in-1-yl) picoline aldehyde oxime 25:

Methyl 3-hydroxy-6- (4- (quinoline-4-ylamino) butyl) picolinate 26:

(2S, 3S, 4R, 5R) -5- (6-amino-9H-purine-9-yl) -3,4-dihydroxy-N- (2- (1-((6- (-(hydroxyimino))) -Methyl) Pyridine-2-yl) Methyl) -1H-1,2,3-triazole-4-yl) Ethyl) Tetrahydrofuran-2-carboxamide hydrochloride 78:

The compound according to any one of claims 1 to 11, which is selected from the above. A method for preparing a compound of the formula (I) according to any one of claims 1 to 12.
In the formula, -XY- is -CH ₂ -CH _2- or -C≡C-, and
A method comprising a Sonogashira coupling reaction between a compound containing 6-bromopyridine aldoxime and a terminal alkyne, and optionally a reduction step by reaction with hydrogen. The compound according to any one of claims 1 to 12, for use in treatment. Treatment of neuropathy and / or respiratory failure due to intoxication with at least one organic phosphorus neuropharmaceutical, and / or treatment of neurological disorders such as Alzheimer's disease and Parkinson's disease, and / or treatment of inflammation, and / or treatment of cancer , And / or the compound according to any one of claims 1 to 12 for use in the treatment of diabetes and / or the treatment of pain.